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Analgesic (sub anesthetic) nitrous oxide interacts with the endogenous opiod system: A review of the evidence
Life Sciences, Vol. 39, pp. 1209-1221 Printed in the U.S.A.
Pergamon Journals
MINIREVIEW ANALGESIC (SUB ENDOGENOUS
ANESTHETIC) NITROUS OXIDE INTERACTS WITH OPIOID SYSTEM : A R E V I E W OF THE E V I D E N C E . M.A.
S.A.Brain
THE
Gillman
Research Institute,173,Louis Botha Orange Grove,2192~South Africa
Ave~
SUMMARY
The concept that anesthesia and analgesia are d i s t i n c t states and t h e r e f o r e are p o s s i b l y mediated by d i f f e r e n t mechanisms is s t r e s s e d . A n a l g e s i c n i t r o u s o x i d e is s h o w n to a c t at s p e c i f i c rather than non specific central nervous system s i t e s , as w e l l as h a v i n g a large number of a c t i o n s s i m i l a r to m o r p h i n e the c l a s s i c a l opioid. This i n c l u d e s the fact that s p e c i f i c o p i o i d a n t a g o n i s t s attenuate the e f f e c t s of ~ o t h m o r p h i n e and analgesic nitrous o x i d e . E v i d e L ~ c e is also provided showing that nitrous o x i d e m a y be a p a r t i a l a g o n i s t and that it m a y i n t e r a c t w i t h the e n d o g e n o u s opioid s y s t e m by the release of endogenous opioids, and /or by d i r e c t a c t i o n at the mu, delta, s i g m a and k a p p a r e c e p t o r s .
INTRODUCTION
The description of the b e h a v i o u r a l and analgesic effects of nitrous oxide by D a v y n e a r l y 2 c e n t u r i e s ago, l e a d to its e v e n t u a l w i d e u s e in m e d i c i n e (i). D e s p i t e its l o n g h i s t o r y of u s a g e as an a n e s t h e t i c and analgesic agent, only recently, has the underlying mechanism of the a n a l g e s i c actions of n i t r o u s oxide begun to be u n d e r s t o o d . This has largely occured through the discovery and characterization of the e n d o g e n o u s opioid system (EOS), since the m i d d l e of the last d e c a d e (2). T h e r e is n o w c o n s i d e r a b l e evidence indicating that a n a l g e s i c n i t rous o x i d e c o u l d act on the EOS(3), e i t , e r d i r e c t l y at the o p i o i d receptor and/or indirectly by stimulating the release of endogenous o p i o i d s to p r o d u c e s o m e of its e f f e c t s ( s e e below). This paper will confine itself to a d i s c u s s i o n of the e v i d e n c e that s o m e of the e f f e c t s of a n a l g e s i c nitrous oxide (concentrat i o n s of n i t r o u s oxide mixed with sufficient oxygen to p r e v e n t a n e s t h e s i a or u n c o n s c i o u s n e s s ) are m e d i a t e d by an i n t e r a c t i o n w i t h the EOS. 0024-3205/86 $3.00 + .00 Copyright (c) 1986 Pergamon Journals Ltd.
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Analgesic Nitrous Oxide and Opioid System
THE .
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IMPORTANCE .
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Vol. 39, No. 14, 1986
ANESTHESIA .
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FROM .
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ANALGESIA. .
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T h e r e h a v e b e e n a c o n s i d e r a b l e n u m b e r of a p p a r e n t l y c o n t r a d i c t o r y findings in the l i t e r a t u r e but close inspection of t h e s e ( 4 - 7 ) indicates that workers have often not made clear distinction between anesthesia and analgesia when comparing results (8,9). T h i s is m o s t important since different mechanisms may mediate these two q u i t e d i f f e r e n t s t a t e s ( 8 , 1 0 ) . In a d d i t i o n , the use of a gas as an e x p e r i m e n t a l a g e n t is a c c o m p a n i e d by a n u m b e r of technical difficulties, w h i c h on t h e i r o w n c o u l d p r o d u c e c o n f l i c t i n g results. These technical problems w i l l be d i s c u s s e d more fully b e l o w . To a v o i d c o n f u s i o n in t h i s a r t i c l e the t e r m anesthesia will be used to d e s c r i b e a state off unconsciousness whilst a n a l g e s i a w i l l be confiiied to the c o n s c i o u s state. THE .
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OPIOID .
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Another area that has confu~ ion and c o n j e c t u r e antagonist effects.
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DEFINITION .
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ANTAGONISTS. .
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for a good o p i o i d s in
deal terms
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Antagonists are u s e d in p h a r m a c o l o g y to c h a r a c t e r i z e the e f f e c t s of d r u g s on p a r t i c u l a r receptor systems. However, since antagonists are s e l d o m 100% s p e c i f i c in all p h y s i o l o g i c a l situations, it is u n w i s e to c o n c l u d e t h a t an e f f e c t a n t a g o n i s e d by a s i n g l e a n t a g o n i s t is m e d i a t e d by a s i n g l e r e c e p t o r c l a s s ( u s u a l l y a n t a g o nised by t h a t particular antagonist). In o r d e r to a v o i d such errors, other criteria have been adopted which~ if m e t , w o u l d strongly support the p o s s i b l e involvement of t h a t particular r e c e p t o r class. In the case of the EOS, n a l o x o n e has b e e n the m o s t commonly e m p l o y e d a n t a g o n i s t at o p i o i d r e c e p t o r s but b l o c k a d e by this a g e n t a l o n e , d o e s not in v i e w of the above, p r o v i d e u n e q u i v o cal p r o o f that an e f f e c t is m e d i a t e d by the EOS. T h u s S a w y n o k et al (Ii) h a v e s u g g e s t e d o t h e r c r i t e r i a (apart f r o m naloxone blockade) t h a t m u s t be f u l f i l l e d in o r d e r to p r o v e E O S involvement in a p a r t i c u l a r r e s p o n s e . T h e s e are : i)
the
demonstration
2) a g e n t s t h a t potentiate 4)
5)
of
cross-tolerance
to
morphine.
i n h i b i t the b r e a k d o w n of e n d o g e n o u s the n a l o x o n e a n t a g o n i s e d r e s p o n s e .
o[her opioid Ealoxone.
antagonists
i s o m e r s of a n t a g o n i s t ~,e i n a c t i v e .
must
having
produce
little
the
opioid
same
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effect
antagonistic
also
as
must
Dosage is a n o t h e r important f a c t o r , to be c o n s i d e r e d when using different antagonists to d e f i n e s p e c i f i c receptor activity. For instance, n a l o x o n e at h i g h d o s e s has b e e n s h o w n to i n t e r a c t w i t h other neurotransmitter systems, a p a r t f r o m the E O S (11). U s i n g the p A 2 ( t h e n e g a t i v e l o g a r i t h m of that c o n c e n t r a t i o n of an a n t a g o n i s t that r e q u i r e s a d o u b l i n g of the c o n c e n t r a t i o n of the a g o n i s t to c o m p e n s a t e for the a c t i o n of the a n t a g o n i s t (12)) v a l u e s for n a l o x o n e and n a l . r e x o n e , Y a k s h and 11owe h a v e p r o v i d e d c o n v i n c i n g
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Analgesic Nitrous Oxide and Opioid System
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evide~Lce from animal work that naloxone w i l l a c t as a s p e c i f i c opioid antagonist at up to 0.3 m g / k g (13). A l t h o u g h o n e m u s t be cautious in e x t r a p o l a t i n g from animal to h u m a n s these d a t a m a k e it p o s s i b l e t h a t for a 7 O k g a d u l t a d o s e r a n g e of n a l o x o n e of as h i g h Es 21 m g w o u l d s t i l l be e x p e c t e d to b l o c k o p i o i d r e c e p t o r s specifically : w h i l s t in the case of n a l t r e x o n e w h i c h is iO t i m e s as p o t e n t as n a l o x o n e (13) the h i g h e s t dose producing specific b l o c k a d e w o u l d be 2.1 mg. W h e r e o p i o i d a n t a g o n i s t s h a v e f a i l e d to antagonise the e f f e c t s of a n a l g e s i c concentrations of n i t r o u s o x i d e it is t h u s c o n c e i v a b l e t h a t the d o s e s of a n t a g o n i s t used m a y have b e e n i n s u f f i c i e n t , p a r t i c u l a r l y in h u m a n w o r k ( s e e below).
EVIDENCE
THAT
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ANALGESIC
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NITROUS
Oxide
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OXIDE
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INTERACTS
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WITH
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EOS
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It h a s b e e n s u g g e s t e d that nitrous oxide along with other anesthetic agents produces its e f f e c t s by n o n - s p e c i f i c CNS d e p r e s s i o n ie. f r o m the c e r e b r u m downwards to the s p i n a l c o r d ( 1 4 ) . T h e r e is now however, evidence that the e f f e c t s of n i t r o u s o x i d e p a r t i c u larly at a n a l g e s i c concentrations are m o r e specific (14). F o r instance nitrous oxide can activate as w e l l as depress central nervous structures(15) and cause anesthesia without causing a depression of limbic neurones(16,17). Furthermore it h a s a l s o b e e n s h o w n to d e p r e s s nociceptive impulses, particularly in the reticular activating s y s t e m w i t h its short a x o n a l s y s t e m s , whilst not a f f e c t i n g fast c o n d u c t i n g oligosynaptic tracts in the b r a i n s t e m ( 1 8 ) . It is s i g n i f i c a n t t h a t the r e t i c u l a r system is an a r e a rich in m o r p h i n e sensitive cells(19). N i t r o u s o x i d e has also b e e n shown to h a v e a l a m i n a specific depressant effect in the d o r s a l h o r n of the s p i n a l c o r d in t h a t nociceptive neurones (in l a m i n a V) a r e d e p r e s s e d , whilst non-nociceptive neurones (in l a m i n a i) are ~ n a f f e c t e d (20). The .
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Oxide .
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Morphine. .
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Previously, this author has presented a considerable b o d y of evid~nce indicating the c l o s e s i m i l a r i t y of the e f f e c t s of the classical opioid morphine a n d t h a t of n i t r o u s o x i d e (14). T h e s e similarities are r e f l e c t e d in t h e ir c o n v u l s a n t , cognitive, motor anti--stress, analgesic, emetic, cardio-respiratory, gastro-intesti n a l and u r o - g e n i t a l e f f e c t s (see ref 14 for f u r t h e r r e f e r e n c e s ) . Furthermore, both agents can produce psychological and physical depel dence(14), and c r o s s t o l e r a n c e has b e e n d e m o n s t r a t e d between these agents. Of c o u r s e it can be a r g u e d that t o l e r a n c e and d e p e n dence occur with non o p i o i d d r u g s as well, but such p h e n o m e n a are a prominent feature of o p i o i d s . Furthermore it is p o s s i b l e to suggest that such effects ( even in the c a s e of n o n o p i o i d s ) are mediated v i a an E O S f i n a l C o m m o n pathway. For these reasons a more detailed discussion of t h e s e p h e n o m e n a was d e e m e d n e c e s s a r y (see b e l o w ) . Nitrous o x i d e h a s a l s o b e e n u s e d as a s u b s t i t u t e for m o r p h i n e as a therapeutic agent, with benefit in a n u m b e r of c o n d i t i o n s including pain states, psychiatric illness(including withdrawal s t a t e s ) and in P a r k i n s o n ' s disease (14,21).
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Vol. 39, No. 14, 1986
MODELS .
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Analgesia.
The first direct evidence relating the analgesic effects of n i t r o u s o x i d e to the E O S w a s the d e m o n s t r a t i o n by B e r k o w i t z et al, that ~oth naloxone and n a l t r e x o n e attentuated nitrous oxide analg e s i a in m i c e (3). T h e y f u r t h e r showed that the a n a l g e s i c effects of n i t r o u s oxide c o u l d be s u p p r e s s e d by m o r p h i n e tolerance (3). These investigators also demonstrated that naloxone attenuated the nitrous oxide induced analgesia b u t n o t that p r o d u c e d by e t h a n o l or a s p i r i n tested on the phenylquinone abdominal constriction assay(22), Nitrous oxide analgesia as a s s e s s e d by the tail-flick test was also attenuated with naloxone in t h i s study(22). The tail-flick test has been shown to be an effective assay particularly of opioid produced analgesia (23). T h e s e analgesic (24,25) effects have been confirmed in o t h e r s t u d i e s . Tolerance .
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Dependence .
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To .
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Oxide.
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A further finding in the s t u d y by B e r k o w i t z et al, w a s t h a t a u t o tolerance could be produced in a n i m a l s by p r i o r exposure to nitrous oxide:a situation that is a n a l o g o u s to t o l e r a n c e produced by m o r p h i n e (22).This auto-tolerance effect has been confirmed by other investigators(26,27). It w a s a l s o s h o w n that this e f f e c t is p r o b a l ly s p e c i f i c since synaptic membrane fatty acid, phospholipid and cholesterol composition of t o l e r a n t mice brain extracts did not differ from non-tolerant controls (27). T h e p o s t u l a t e that nitrous oxide tolerance is a s p e c i f i c effect is f u r t h e r u n d e r l i n e d since mice tolerant to n i t r o u s o x i d e do n o t s h o w c r o s s tolerance to I arbiturates (28)~ Moreover an enkephalinase inhibitor(phosphoramidon) has been shown to p r e v e n t tolerance development to the a n a l g e s i c e~fects of n i t r o u s oxide;indicating that the EOS may become underactive during the development of tolerance to t h e g a s ( 1 0 ) . In a d d i t i o n acute dependence to t h e effects of n i t r o u s oxide in m i c e has also been demonstrated. Exposures of as l i t t l e as 30 m i n u t e s to 50% n i t r o u s oxide results in w i t h d r a w a l convulsions (29). F u r t h e r m o r e , Manson et al, h a s show~ that naloxone can precipitate an o p i o i d - l i k e withdrawal s t a t e in m i c e a f t e r a s i n g l e e x p o s u r e to 70% n i t r o u s o x i d e for 30 minutes (30). M o r e o v e r , these workers also demonstrated that this withdrawal response to n i t r o u s oxide was blunted if m o r p h i n e was given instead of naloxone. Other workers prior to this however,were unable to c a u s e a n a b s t i n e n c e syndrome with either naloxone or na Itrexone following exposure to t h e gas; and suggested t h a t the p h y s i c a l dependence on n i t r o u s oxide was more closely related to t h a t of e t h a n o l than morphine(31). This work however showed methadological differences, when compared to the otne~ study(30). Possibly the m o s t important of w h i c h were that the o p i o i d a n t a g o n i s t was given after removal of the a n i m a l s from the g a s exposure; and also higher concentrations and longer gas exposures were used (31). In addition tolerance and physical dependence may be d i s s o c i a t e d under certain conditions; for instance naloxone h a s f a i l e d to p r e c i p i t a t e a withdrawal sign when given to a h i g h l y tolerant vas de ferens preparat ions(32). Furthermore nitrous oxide can attenuate the m o r p h i n e abstinence
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Analgesic Nitrous Oxide and Opioid System
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syndrome in r a t s ( 3 3 ) . E v i d e n c e has also been presented~in a study s t i l l to be c o n f i r m e d by o t h e r s , that rats tolerant to n i t r o u s o x i d e w e r e not t o l e r a n t to the a n a l g e s i c e f f e c t s of m o r p h i n e (34). This linding appears to be difficult to e x p l a i n however such unidirectional cross tolerance~ has b e e n o b s e r v e d to o c c u r b e t e e n m o r p h i n e and o t h e r o p i o i d s s u c h as h e r o i n and e t o r p h i n e ( 3 5 ) . Further evidence in f a v o u r of EOS i n v o l v e m e n t in the d e v e l o p m e n t of t o l e r a ~ c e and d e p e n d e n c e to n i t r o u s o x i d e ~ is the f i n d i n g that 18 h o u r s of e x p o s u r e to 7 5 - 8 0 % nitrous oxide resulted in a decrease of o p i o i d receptor density~ as m e a s u r e d at (3H) dihydromorphine b i n d i n g a s s a y s of rat b r a i n s t e m (36). F u r t h e r m o r e (3H)-raloxone binding is d e c r e a s e d a f t e r i h o u r of n i t r o u s oxide exposure in m i c e not resistant to the locomotor effects of morphine, whilst in c o n t r a s t ~ resistant mice did not show this e f f e c t (37). Locomotor .
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Nitrous
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Oxide.
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The locomotor stimulating effects of n i t r o u s oxide which are s i m i l a r to t h o s e p r o d u c e d by m o r p h i n e can a l s o be a t t e n u a t e d by both naltrexone and n a l o x o n e as w e l l as m o r p h i n e t o l e r a n c e (38). It m u s t be e m p h a s i z e d however, t h a t the a n a l g e s i c and locomotor effects of n i t r o u s oxide are different f r o m t h o s e of m o r p h i n e : highel c o n c e n t r a t i o n s of n a l o x o n e are r e q u i r e d to a n t a g o n i s e n i t ous o x i d e a n a l g e s i a , than are r e q u i r e d to reverse these effects of morphine (22). In a d d i t i o n , the l o c o m o t o r e f f e c t s of n i t r o u s o x i d e are not c o m p l e t e l y a b o l i s h e d by n a l o x o n e or n a l t r e x o n e (34). However this may indicate t h a t the g a s interacts with opioid receptors that are resistant to a n t a g o n i s m by these agents,such as kappa~ sigma or delta receptor s(39).Ano ther possibility is t h a t the g a s c a u s e s the r e l e a s e of e n d o g e n o u s o p i o i d p e p t i d e s ( s e e b e l o w ) w h i c h are m o r e r e s i s t a n t to a n t a g o n i s m by b l o c k i n g a g e n t s t h a n are e x o g e n o u s o p i o i d s ( 4 0 ) . Mice resistant to the l o c o m o t o r activity effects of m o r p h i n e have also been demor strated to be r e s i s t a n t to t h e s e e f f e c t s of n i t r o u s oxide (38). M o r e o v e r the c a t e c h o l a m i n e r g i c mechanisms that a p p e a r to be important in p r o d u c i n g the l o c o m o t o r e f f e c t s of b o t h m o r p h i n e and n i t r o u s o x i d e are s i m i l a r s i n c e these e f f e c t s are r e d u c e d by b o t h alpha-methyl-p-tyrosine and h a l o p e r i d o l administration(41). Release .
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Endogenous .
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Opioids .
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Met-enkephalin but not leu-enkephalin l e v e l s h a v e b e e n s h o w n to be raised in t h e CSF of a n i m a l s exposed to n i t r o u s oxide (42)~however nitrous oxide exposure failed to c h a n g e metenke~ahalin l e v e l s in v a r i o u s b r a i n a r e a s in w o r k d o n e by o t h e r s (43). H o w e v e r , the l a t t e r finding could reflect no c h a n g e in stored neurotransmitter d e s p i t e long l a s t i n g r e l e a s e . T h i s idea is s u p p o r t e d by a n o t h e r a n i m a l s t u d y w h i c h has s h o w n that w h i l s t plasi~a b e t a - e n d o r p h i n levels were raised~ brain levels remained u n c h ~ n g e d d u r i n g n i t r o u s o x i d e e x p o s u r e (44). It is i n t e r e s t i n g to n o t e that in a h u m a n s t u d y n e i t h e r l e u - e n k e p h a i n or b e t a - e n d o r p h i n l e v e l s are r a i s e d in CSF d u r i n g n i t r o u s o x i d e a d m i n i s t r a t i o n (45). Unfortunately met-enkephalin l e v e l s w e r e not m e a s u r e d in the latter study. T h e s e c o n t r a d i c t o r y f i n d i n g s i n d i c a t e that f u r t h e r w o r k is n e c e s s a r y in this a r e a to c l a r i f y t h e s e i s s u e s .
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In v i t r o r a d i o - r e c e p t o r binding studies have demonstrated that nitrous oxide interferes with both 3(H)-dihydromorphine (46,47) and (3H)-naloxone binding(48)~ indicating that nitrous oxide interacts with the m u o p i o i d receptor as h a s b e e n p r e v i o u s l y suggested(49). Furthermore nitrous oxide produces a significant s h i f t in the IC50 v a l u e d e t e r m i n e d from (3)H-leuenkephalin binding experiments suggesting activity at the d e l t a binding s i t e as well(S7). These workers demonstrated that the gas had no e f f e c t on b i u d i n g at the k a p p a or s i g m a o p i o i d r e c e p t o r or at the G A B A site. The ligands used in this work were (3)He t h y ike t o c y c laz oc ine ,( 3 ) H - N - A I l y l - N - N o r m e t a z o c i n e ( S K F - l O , 0 4 7 ) and (3)H-~ u s c i m o l respectively (47). This data would appear to i n d i c a t e that the e f f e c t s of the gas are h i g h l y s p e c i f i c e v e n w i t h r e s p e c t to the o p i o i d r e c e p t o r . L a w r e n c e and L i v i n g s t o n , however w e r e u n a b l e to i n f l u e n c e (3H)- d i h y r o m o r p h i n e binding with nitrous oxide; h o w e v e r , it is not c l e a r h o w the n i t r o u s o x i d e w a s a p p l i e d to t h e i r a l i q u o t s . If t h e n i t r o u s o x i d e w a s s o l u b o l i z e d in o l i v e oil as seems likely Ifrom their description) this may have interfered with their results (25). F u r t h e r w o r k is s t i l l q u i t e c l e a r l y r e q u i r e d in this a r e a to c l a r i f y these d i s p a r a t e f i n d i n g s . Isolated .
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Isolated organ bath experiments i n v o l v i n g use of n i t r o u s o x i d e and gut preparations have provided negative results (Dreyer and Gillman, unpublished observations ; Ngai and Finck unpublished observations (36). T h e s e n e g a t i v e results are probably the m o s t serious f l a w in the h y p o t h e s i s that n i t r o u s o x i d e i n t e r a c t s w i t h opioid receptors,since i s o l a t e d o r g a n s are used as the c l a s s i c a l o p i o i d assay. H o w e v e r these n e g a t i v e f i n d i n g s are p r o b a b l y due to the practical difficulties of w o r k i n g with a gas in t h i s s i t u a t i o n . For i n s t a n c e n i t r o u s o x i d e is c o n s i d e r a b l y m o r e s o l u b l e than o x y g e n in b o t h w a t e r and lipids(50). T h i s w o u l d lead to r a p i d saturation of b o t h b u f f e r and and tissue within the o r g a n b a t h resulting in a n o x i a if the g a s e s are a p p l i e d at n o r m a l a n a l g e s i c conc~:ntrations(eg.50% nitrous oxide:50% o x y g e n ) . S u c h an a n o x i c p r e p a r a t i o n m i g h t c a u s e the o r g a n to b e c o m e t o t a l l y u n r e s p o n s i v e ; as w e f o u n d in o u r e x p e r i m e n t s ( D r e y e r and Gillman; unpublished observations) • In this r e g a r d it is n o t e w o r t h y that in e x p e r i m e n t s w i t h dogs that a n o x e m i c i r r e g u l a r c o n t r a c t i o n s of the gut w e r e o b s e r v e d f o l l o w i n g the a p p l i c a t i o n of a n e s t h e t i c c o n c e n t r a t i o n s of n i t r o u s oxide. If however a breath or t w o of o x y g e n w a s g i v e n t h e s e c o n t r a c t i o n s disappeared(51). Apart from the a n o x i c effect that may follow because of the solubility differences the rapid saturation of the organ by nitrous oxide within the bath could conceivably g i v e r i s e to rapid acute tolerance development; an e f f e c t that has b e e n s h o w n to occur with morphine within 3 minutes(52). It is d i f f i c u l t in v i e w of the f o r e g o i n g to v i s u a l i z e a m e t h o d of p r o v i d i n g a d e q u a t e
Vol. 39, No. 14, 1986
Analgesic Nitrous Oxide and Opioid System
1215
levels of n i t r o u s oxide without running the r i s k s of p r o d u c i n g acute tolerance, w h i c h m a y be f o l l o w e d by anoxia. We are at the moment investigating the p o s s i b i l i t y of p r e v e n t i n g this rapid a c c u m l ~ l a t i o n of n i t r o u s o x i d e w i t h i n the p r e p a r a t i o n . An interesting finding that may also be significant is t h a t using infra-red spectroscopy nitrous oxide has been shown to attach to 2 d i s t i n c t sites; one polar and associated with the aqueo~is p h a s e a n d the o t h e r non-polar and linked to the l i p i d phase!53). T h i s m a y w e l l be s i g n i f i c a n t s i n c e it h a s b e e n suggeste~i t h a t the o p i o i d r e c e p t o r is c o m p o s e d of d i s t i n c t protein and lipid areas(54). HUMAN .
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The first p u b l i s h e d d e m o n s t r a t i o n in m a n that an a n a l g e s i c e f f e c t of n i t r o u s o x i d e c o u l d be r e v e r s e d by n a l o x o n e w a s t h a t in w h i c h the c e r e b r a l e v o k e d p o t e n t i a l to p a i n was used as the i n d i c a t o r of analgesia(55). S o o n a f t e r this, o t h e r w o r k e r s s h o w e d that low dose naloxone could attenuate nitrous oxide analgesia using acute experimental p a i n ( 5 6 , 5 7 ) as w e l l as c h r o n i c pain(49). In a n o t h e r study, using post-operative pain, the a n a l g e s i c response produced by n i t r o u s o x i d e c o u l d n o t be r e v e r s e d by n a l o x o n e ( 5 8 ) , however, these w o r k e r s f a i l e d to m a k e s u f f i c i e n t allowance for p h a r m a c o k i netic differences caused by the c o n t i n u o u s administration of nitrcus oxide and the extremely shor t half life of naloxone(59),since they assesed pain thresholds only after 40 minutes had e l a p s e d f r o m the time of n a l o x o n e a d m i n i s t r a t i o n ( 5 9 ) . It ha~ b e e n d e m o n s t r a t e d t h a t the c o n c e n t r a t i o n of n a l o x o n e in the C N S r i s e s r a p i d l y following i.v. b o l u s i n j e c t i o n ,but t h e s e l e v e l s are e v a n e s c e n t ( 6 0 ) . T h i s d o e s n o t a p p l y to m o r p h i n e where peak brain levels are reached more slowly but maintained much longel. These pharmacokinetics differences have b e e n u s e d to exp l a i n the p o t e n t but s h o r t - l i v e d morphine antagonistic e f f e c t of naloxone(61). Since nitrous oxide was given continuously during these e x p e r i m e n t s ( 5 8 ) it is p o s s i b l e that the a n t a g o n i s t i c effects of n a l o x o n e in this case c o u l d have b e e n e v e n s h o r t e r - a c t i n g than under normal circumstances(59). In the case of m o r p h i n e peak b r a i n l e v e l s o c c u r for up to 2 h o u r s , w h i l s t t h o s e of n a l o x o n e b e g i n to wane rapidly a f t e r a b o u t 15 m i n u t e s ( 6 0 ) . The i m p o r t a n c e of t h e s e pharmacokinetic diferrences appears to be b o r n e o u t by o u r f i n dingsin which the e f f e c t s of n a l o x o n e b e g a n to d i m i n i s h after 3 minutes disappearing completely within i0 m i n u t e s ; this during continuous analgesic nitrous oxide administration(56). It w o u l d thus a p p e a r that the c o n t r a d i c t o r y w o r k on c h r o n i c pain(58) o n l y "serves to c o n f u s e the i s s u e " ( 6 2 ) . A m o r e r e c e n t s t u d y in w h i c h naloxone(at low d o s e s ( l . 2 m g ) and i n j e c t e d s l o w l y over a 2-4 m i n u t e p e r i o d ) f a i l e d to r e v e r s e n i t r o u s o x i d e a n a l g e s i a of a n o c i c e p t i v e brain stem reflex also appears to s u f f e r from pharmacokinetic defects. In this w o r k the n e g a t i v e results were probably related to t h e i n a d e q u a t e d o s e s of a n t a g o n i s t used(63). This highlights the i m p o r t a n c e of u s i n g d o s e s of o p i o i d a n t a g o n i s t h i g h e n o u g h to effectively b l o c k all c l a s s e s of o p i o i d r e c e p t o r but at the s a m e t i m e not h i g h e n o u g h so that that s p e c i f i c i t y for these r e c e p t o r s is lost.
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Haugen et al (64) d e m o n s t r a t e d that the analgesia produced by nitrous oxide during painful tooth stimulation (at the same concentrations) decreased after a number of experimental runs. These workers suggested that this effect was caused by l e a r n i n g . H o w e v ~ r~ s o m e of t h e s e e x p e r i m e n t a l runs occurred a f t e r o n l y a IO minute rest period~ and it is t h e r e f o r e possible, and even likely that these results were a manifestation of a c u t e t o l e r a n c e to the gas. f u r t h e r m o r e , other workers(65) have also demonstrated acute tolerEnce to the a n a l g e s i c effects of n i t r o u s oxide, inasmuch as contiruous administration of 33% n i t r o u s o x i d e for I h o u r r e s u l t e d in p a i n t h r e s h o l d s being t h e s a m e at t h e b e g i n n i n g of as at t h e e n d of t h e e x p e r i m e n t in s o m e subjects. However, these workers w e r e ~ b l e to p r e v e n t the d e v e l o p m e n t of this a c u t e t o l e r a n c e if a 50% concentration of n i t r o u s oxide was arrived at b y g r a d u a l increnents o v e r a 45 m i n u t e period. If t h e s e g r a d u a l increments were used, the effect of n i t r o u s oxide w a s to i n c r e a s e the pain threshold twofold. This implies that a c u t e t o l e r a n c e to a s i n g l e concentration of nitrous oxide can occur within an hour. Abuse .
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Although many paradigms have been devised to s h o w t h a t s e l f a d ministration of morphine in a n i m a l s is s u g g e s t i v e of abuse potential~ only recently have such experiments b e e n u s e d in the c a s e of nitrous oxide. W o o d et a i ( 6 6 ) h a v e c l e a r l y demonstrated such behaviour in the s q u i r r e l monkey. The human abuse potential of n i t r o u s oxide has been known ever since the euphoriant effects of t h e g a s w a s first described by Davy. In a d d i t i o n , a s t u d y by R o s e n b e r g et al i n v o l v i n g 524 m e d i cal and dental students who responded to a q u e s t i o n a i r e indicated t h a t 20% of t h e s e s t u d e n t s had utilised n i t r o u s o x i d e at s o m e t i m e to o b t a i n "a h i g h " ( 6 7 ) . Therapeutic .
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Kripke and Hechtman(68) described a c a s e of p e n t a z o c i n e addiction whic~ was successfully treated with analgesic concentrations of nitrous oxide; further demonstrating that nitrous o x i d e is c a p a b l e of being u s e d as a substitute for a known opioid agent in t h e treatment of a w i t h d r a w a l state. G i l l m a n and Lichtigfeld (69) h a v e successfully treated 2 c a s e s of o p i o i d addiction and withdrawal usin~ analgesic nitrous oxide. It t h u s a p p e a r s that nitrous oxide may prove to be a u s e f u l tool for the treatment of o p i a t e withdrawal states(70)~ which merits further investigation.
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A C T I O N OF A N A L G E S I C W I T H THE E O S
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There has been some debate not only regarding the possibility nitrous oxide interacts w i t h the E O S b u t a l s o w h e t h e r this occurs directly (as a n a g o n i s t on opioid receptors) as proposed by Gillman and Lichtigfeld(49,59,71) or i n d i r e c t l y as postulated by
Vol. 39, No. 14, 1986
Analgesic Nitrous Oxide and Opioid System
1217
others that these effects of n i t r o u s oxide are mediated via release of e n d o g e n o u s opioids (22~36,38,42). These ideas h o w e v e r are not m u t u a l l y exclusive, since it is p o s s i b l e that b o t h m e c h a nisms m a y be i n v o l v e d , as has been s h o w n to o c c u r in the case of morphine (72). The e x a c t m e c h a n i s m of a c t i o n of n i t r o u s o x i d e at the o ~ i o i d receptor c a n n o t at p r e s e n t be f i n a l l y described, but this author (73) h a s suggested 3 possible mechanisms. First n i t r o u s o x i d e c o u l d act d i r e c t l y as an a g o n i s t in a m a n n e r a n a l a gous to that of t e t r a m e t h y l - a m m o n i u m , which although a very small molecule is a n i c o t i n i c agonist. Second,itis possible that the Nitrogen and Oxygen (which appeared to be k e y a t o m s for o p i o i d activity) of 2 d i f f e r e n t nitrous oxide molecules might lock simulultaneously into the 2 key a r e a s on the o p i o i d r e c e p t o r , thus producing its o p i o i d effects. The work of C a u g h e y et al (53) demonstrating the d i s t r i b u t i o n of n i t r o u s o x i d e in b o t h the lipid and a q u e o u s p h a s e s u p p o r t this c o n c e p t and w o u l d a c c o r d w i t h the known chemistry of N i t r o g e n and Oxygen. Third, a non specific e f f e c t at the r e c e p t o r such as o x i d a t i o n , may activate the o p i o i d receptor (see ref 73for d e t a i l s of t h e s e mechanisms). It is also p o s s i b l e to p o s t u l a t e that n i t r o u s o x i d e m a y act as a partial agonist (competitive dualist). Maruyama et al (74) u s i n g the e l e c t r o - s p i n o g r a m w e r e able to d e m o n s t r a t e that n i t r o u s o x i d e tended to r e d u c e the e f f e c t s of m o r p h i n e in t h e i r e x p e r i m e n t s . Furthermore, ketamine analgesia has b e e n s h o w n to act via o p i a t e receptors (75), a n d a n e s t h e t i c requirements of k e t a m i n e are red u c e d in the p r e s e n c e of n i t r o u s o x i d e (76).This indicates, that ketamine and nitrous oxide may act synergistically at the opioid receptor(14). In v i e w of t h e s e f i n d i n g s nitrous oxide may a c t as a p a r t i a l agonist ( or c o m p e t i t i v e dualist) at the o p i o i d receptor(14). In t h i s r e s p e c t it is s i m i l a r to p e n t a z o c i n e which is a l ~ o a p a r t i a l agonist (77). It is t h e r e f o r e significant that n i t r o u s o x i d e has b e e n used to ameliorate the a b s t i n e n c e s y n d r o m e caused by a p e n t a z o c i n e addiction (68). S i n c e p e n t a z o c i n e is an a g o n i s t at the k a p p a r e c e p t o r (77), it is c o n c e i v a b l e that n i t r o u s oxide may also have activity at t h i s as w e l l as the m u r e c e p t o r . Further evidence indicating that n i t r o u s o x i d e i n t e r a c t s w i t h the k a p p a r e c e p t o r is p r o v i d e d by H y m e s and H y m s o n w h o h a v e s h o w n that nitrous oxide generalizes to a d i s c r i m i n a t i v e s t i m u l u s p r o v i d e d by ethylketocyclazocine which is a kappa agonist but not morphine(78).The fact that high doses of n a l o x o n e are required to antagonise n i t r o u s o x i d e a n a l g e s i a than are r e q u i r e d to a n t a g o n i s e that of m o r p h i n e adds further support to the postulate that nitrous oxide is a k a p p a agonist or c a u s e s the r e l e a s e of the endog~ nous l i g a n d for the k a p p a r e c e p t o r , s i n c e b o t h mu and k a p p a receptors appear to be i n v o l v e d in o p i o i d analgesia(79); and naloxone has much less affinity for the k a p p a t h a n for the mu receptor (39). Thus one would expect it to require higher concentrations of n a l o x o n e to block kappa receptor effects initiated by n i t r o u s oxide. Furthermore~ since neither naloxone nor naltrexone can entirely abolish the locomotor effects of nitrous oxide(38) this m i g h t i n d i c a t e a n o t h e r r e c e p t o r a p a r t f r o m the m u r e c e p t o r is i n v o l v e d in m e d i a t i n g p a r t of t h e s e e f f e c t s . This is in a g r e e m e n t w i t h the f i n d i n g s of l w a m o t a , w h o has s h o w n that both the m u and sigma receptor are involved in o p i o i d p r o d u c e d l o c o m o t o r a c t i v i t y (79). M o r e o v e r the s i g m a r e c e p t o r can under certain conditions be r e s i s t a n t to n a l o x o n e and n a l t r e x o n e blockade (80). If n i t r o u s oxide is a c t i v e via sigma mediated mechanisms as w e l l this m a y e x p l a i n the i n a b i l i t y of n a l o x o n e to
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Analgesic Nitrous Oxide and Opioid System
e te ly
block
the
locomotor
Vol. 39, No. 14, 1986
e f fect
s
of
the
gas.
CONCLUSIONS .
Of the 5 criteria suggested by S a w y n o k et a l ( ~ l ) t o be to s a t i s f y the r e q u i r e m e n t s for d e f i n i t i o n as an o p i o i d h a v e b e e n m e t viz : i)
the
demonstration
2)
evidence
3)
other opioid antagonists s a n e e f f e c t s as n a l o x o n e .
for
the
of
cross-tolerance
direct
release (in
of
this
necessary agonist 3
to m o r p h i n e . opioid case
peptides.
naltrexone)
produce
the
In a d d i t i o n in v i t r o binding studies (46,47,48) add further e v i d e n c e for the h y p o t h e s i s that some of the e f f e c t s of a n a l g e s i c n i t r o r s o x i d e are m e d i a t e d via an i n t e r a c t i o n w i t h the EOS. T h e s e latter data according to H u g h e s and K o s t e r l i t z provides final confirmation of of an agents interaction with opioid receptors(81). Therefore it w o u l d appear that 3 more criteria n e e d I o be m e t b e f o r e the h y p o t h e s i s that a n a l g e s i c n i t r o u s o x i d e inter~ cts w i t h o p i o i d r e c e p t o r s is f i n a l l y proven~ n a m e l y : I)
It m u s t p r o d u c e a dose of m o u s e vas d e f e r e n s , pig i l e u m ( 7 8 ) .
2)
The agonist fic(ll,78).
3)Agents that potentiate
and
related inhibition cat n i c t i t a t i n g
antagonist
effects
of n e r v e membrane
must
be
contractions and g u i n e a -
stereospeci-
i n h i b i t the b r e a k d o w n of e n d o g e n o u s opioids the n a l o x o n e antagonised response(ll).
also
In c o n c l u s i o n ~ a l t h o u g h e v i d e n c e is still l a c k i n g and s o m e i m p o r tant investigations must s t i l l be u n d e r t a k e n there is a l r e a d y considerable experimental support for the c o n c e p t that analgesic nitrous oxide interacts with the E O S to p r o d u c e some of its pharmacological effects. Furthermore, it is p o s s i b l e to s p e c u l a t e that nitrous oxide interacts directly and/or indirectly(i.e.by r e l e s s i n g e n d o g e n o u s o p i o i d s ) not only w i t h the mu, but w i t h o t h e r opioid receptors v i z . t h e d e l t a , k a p p a and s i g m a r e c e p t o r s . This non s p e c i f i c i t y in r e l a t i o n to o p i o i d r e c e p t o r s m a y be c o n s i s t a n t with the p o s s i b i l i t y that nitrous oxide was conceivably the primordial opioid substance(82,83). Acknowledgements
Part of t h i s work was presented by the a u t h o r in the T h e s i s "NITROUS OXIDE AS AN O P I O I D AGONIST : SOME EXPERIMENTAL AND CLINICAL APPLICATIONS". presented in fulfilment of the requirements for the d e g r e e D.Sc. at P o t c h e f s t r o o m University, South Africa. S u p p o r t e d by a g r a n t from A n g l o - A m e r i c a n and De B e e r s C o r p o r a t i o n of S o u t h Africa. Mrs M a r t h a O p p e n h e i m is t h a n k e d for s k i l l f u l p r o o f - r e a d i n g .
Vol. 39, No. 14, 1986
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1219
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13. 14.
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Analgesic Nitrous Oxide and Opioid System
Vol. 39, No. 14, 1986
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Y A N G JC, C L A R K W C , N G A I S H . A n e s t h e s i o l o g y , 52:414-417(1980). L E V I N E J, G O R D O N NC, F I E L D S H L . P a i n , 13:165-170(1982). GILLMAN MA,LICHTIGFELD FJ. Pain 1 7 : 1 0 3 - 1 0 4 ( 1 9 8 3 ) . BERKOWITZ BA, NGAI S H , H E M P S T E A D J , S P E C T O R SJ.J P h a r m a c o l Exp Ther, 195:499-504(1975). N G A I SH, B E R K O W I T Z BA, Y A N G JC, H E M P S T E A D BS, S P E C T O R SJ. Anesthesiology, 44:398-401(1976). O W E N S WD. S u r v e y of A n e s t h e s i o l o g y , 27: 137(1983). W I L L E R J-C, B E R G E R E T S, G A U D Y J-H, D A U T H I E R C . A n e s t h e s i o l o g y , 63:467-472(1985). H~UGEN PO, C O P P O C K W J , B E R Q U I S T HC.Anesthesiology, 20: 321324(1959).
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MINIREVIEW ANALGESIC (SUB ENDOGENOUS
ANESTHETIC) NITROUS OXIDE INTERACTS WITH OPIOID SYSTEM : A R E V I E W OF THE E V I D E N C E . M.A.
S.A.Brain
THE
Gillman
Research Institute,173,Louis Botha Orange Grove,2192~South Africa
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SUMMARY
The concept that anesthesia and analgesia are d i s t i n c t states and t h e r e f o r e are p o s s i b l y mediated by d i f f e r e n t mechanisms is s t r e s s e d . A n a l g e s i c n i t r o u s o x i d e is s h o w n to a c t at s p e c i f i c rather than non specific central nervous system s i t e s , as w e l l as h a v i n g a large number of a c t i o n s s i m i l a r to m o r p h i n e the c l a s s i c a l opioid. This i n c l u d e s the fact that s p e c i f i c o p i o i d a n t a g o n i s t s attenuate the e f f e c t s of ~ o t h m o r p h i n e and analgesic nitrous o x i d e . E v i d e L ~ c e is also provided showing that nitrous o x i d e m a y be a p a r t i a l a g o n i s t and that it m a y i n t e r a c t w i t h the e n d o g e n o u s opioid s y s t e m by the release of endogenous opioids, and /or by d i r e c t a c t i o n at the mu, delta, s i g m a and k a p p a r e c e p t o r s .
INTRODUCTION
The description of the b e h a v i o u r a l and analgesic effects of nitrous oxide by D a v y n e a r l y 2 c e n t u r i e s ago, l e a d to its e v e n t u a l w i d e u s e in m e d i c i n e (i). D e s p i t e its l o n g h i s t o r y of u s a g e as an a n e s t h e t i c and analgesic agent, only recently, has the underlying mechanism of the a n a l g e s i c actions of n i t r o u s oxide begun to be u n d e r s t o o d . This has largely occured through the discovery and characterization of the e n d o g e n o u s opioid system (EOS), since the m i d d l e of the last d e c a d e (2). T h e r e is n o w c o n s i d e r a b l e evidence indicating that a n a l g e s i c n i t rous o x i d e c o u l d act on the EOS(3), e i t , e r d i r e c t l y at the o p i o i d receptor and/or indirectly by stimulating the release of endogenous o p i o i d s to p r o d u c e s o m e of its e f f e c t s ( s e e below). This paper will confine itself to a d i s c u s s i o n of the e v i d e n c e that s o m e of the e f f e c t s of a n a l g e s i c nitrous oxide (concentrat i o n s of n i t r o u s oxide mixed with sufficient oxygen to p r e v e n t a n e s t h e s i a or u n c o n s c i o u s n e s s ) are m e d i a t e d by an i n t e r a c t i o n w i t h the EOS. 0024-3205/86 $3.00 + .00 Copyright (c) 1986 Pergamon Journals Ltd.
1210
Analgesic Nitrous Oxide and Opioid System
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Vol. 39, No. 14, 1986
ANESTHESIA .
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T h e r e h a v e b e e n a c o n s i d e r a b l e n u m b e r of a p p a r e n t l y c o n t r a d i c t o r y findings in the l i t e r a t u r e but close inspection of t h e s e ( 4 - 7 ) indicates that workers have often not made clear distinction between anesthesia and analgesia when comparing results (8,9). T h i s is m o s t important since different mechanisms may mediate these two q u i t e d i f f e r e n t s t a t e s ( 8 , 1 0 ) . In a d d i t i o n , the use of a gas as an e x p e r i m e n t a l a g e n t is a c c o m p a n i e d by a n u m b e r of technical difficulties, w h i c h on t h e i r o w n c o u l d p r o d u c e c o n f l i c t i n g results. These technical problems w i l l be d i s c u s s e d more fully b e l o w . To a v o i d c o n f u s i o n in t h i s a r t i c l e the t e r m anesthesia will be used to d e s c r i b e a state off unconsciousness whilst a n a l g e s i a w i l l be confiiied to the c o n s c i o u s state. THE .
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Antagonists are u s e d in p h a r m a c o l o g y to c h a r a c t e r i z e the e f f e c t s of d r u g s on p a r t i c u l a r receptor systems. However, since antagonists are s e l d o m 100% s p e c i f i c in all p h y s i o l o g i c a l situations, it is u n w i s e to c o n c l u d e t h a t an e f f e c t a n t a g o n i s e d by a s i n g l e a n t a g o n i s t is m e d i a t e d by a s i n g l e r e c e p t o r c l a s s ( u s u a l l y a n t a g o nised by t h a t particular antagonist). In o r d e r to a v o i d such errors, other criteria have been adopted which~ if m e t , w o u l d strongly support the p o s s i b l e involvement of t h a t particular r e c e p t o r class. In the case of the EOS, n a l o x o n e has b e e n the m o s t commonly e m p l o y e d a n t a g o n i s t at o p i o i d r e c e p t o r s but b l o c k a d e by this a g e n t a l o n e , d o e s not in v i e w of the above, p r o v i d e u n e q u i v o cal p r o o f that an e f f e c t is m e d i a t e d by the EOS. T h u s S a w y n o k et al (Ii) h a v e s u g g e s t e d o t h e r c r i t e r i a (apart f r o m naloxone blockade) t h a t m u s t be f u l f i l l e d in o r d e r to p r o v e E O S involvement in a p a r t i c u l a r r e s p o n s e . T h e s e are : i)
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as
must
Dosage is a n o t h e r important f a c t o r , to be c o n s i d e r e d when using different antagonists to d e f i n e s p e c i f i c receptor activity. For instance, n a l o x o n e at h i g h d o s e s has b e e n s h o w n to i n t e r a c t w i t h other neurotransmitter systems, a p a r t f r o m the E O S (11). U s i n g the p A 2 ( t h e n e g a t i v e l o g a r i t h m of that c o n c e n t r a t i o n of an a n t a g o n i s t that r e q u i r e s a d o u b l i n g of the c o n c e n t r a t i o n of the a g o n i s t to c o m p e n s a t e for the a c t i o n of the a n t a g o n i s t (12)) v a l u e s for n a l o x o n e and n a l . r e x o n e , Y a k s h and 11owe h a v e p r o v i d e d c o n v i n c i n g
Vol. 39, No. 14, 1986
Analgesic Nitrous Oxide and Opioid System
1211
evide~Lce from animal work that naloxone w i l l a c t as a s p e c i f i c opioid antagonist at up to 0.3 m g / k g (13). A l t h o u g h o n e m u s t be cautious in e x t r a p o l a t i n g from animal to h u m a n s these d a t a m a k e it p o s s i b l e t h a t for a 7 O k g a d u l t a d o s e r a n g e of n a l o x o n e of as h i g h Es 21 m g w o u l d s t i l l be e x p e c t e d to b l o c k o p i o i d r e c e p t o r s specifically : w h i l s t in the case of n a l t r e x o n e w h i c h is iO t i m e s as p o t e n t as n a l o x o n e (13) the h i g h e s t dose producing specific b l o c k a d e w o u l d be 2.1 mg. W h e r e o p i o i d a n t a g o n i s t s h a v e f a i l e d to antagonise the e f f e c t s of a n a l g e s i c concentrations of n i t r o u s o x i d e it is t h u s c o n c e i v a b l e t h a t the d o s e s of a n t a g o n i s t used m a y have b e e n i n s u f f i c i e n t , p a r t i c u l a r l y in h u m a n w o r k ( s e e below).
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It h a s b e e n s u g g e s t e d that nitrous oxide along with other anesthetic agents produces its e f f e c t s by n o n - s p e c i f i c CNS d e p r e s s i o n ie. f r o m the c e r e b r u m downwards to the s p i n a l c o r d ( 1 4 ) . T h e r e is now however, evidence that the e f f e c t s of n i t r o u s o x i d e p a r t i c u larly at a n a l g e s i c concentrations are m o r e specific (14). F o r instance nitrous oxide can activate as w e l l as depress central nervous structures(15) and cause anesthesia without causing a depression of limbic neurones(16,17). Furthermore it h a s a l s o b e e n s h o w n to d e p r e s s nociceptive impulses, particularly in the reticular activating s y s t e m w i t h its short a x o n a l s y s t e m s , whilst not a f f e c t i n g fast c o n d u c t i n g oligosynaptic tracts in the b r a i n s t e m ( 1 8 ) . It is s i g n i f i c a n t t h a t the r e t i c u l a r system is an a r e a rich in m o r p h i n e sensitive cells(19). N i t r o u s o x i d e has also b e e n shown to h a v e a l a m i n a specific depressant effect in the d o r s a l h o r n of the s p i n a l c o r d in t h a t nociceptive neurones (in l a m i n a V) a r e d e p r e s s e d , whilst non-nociceptive neurones (in l a m i n a i) are ~ n a f f e c t e d (20). The .
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Previously, this author has presented a considerable b o d y of evid~nce indicating the c l o s e s i m i l a r i t y of the e f f e c t s of the classical opioid morphine a n d t h a t of n i t r o u s o x i d e (14). T h e s e similarities are r e f l e c t e d in t h e ir c o n v u l s a n t , cognitive, motor anti--stress, analgesic, emetic, cardio-respiratory, gastro-intesti n a l and u r o - g e n i t a l e f f e c t s (see ref 14 for f u r t h e r r e f e r e n c e s ) . Furthermore, both agents can produce psychological and physical depel dence(14), and c r o s s t o l e r a n c e has b e e n d e m o n s t r a t e d between these agents. Of c o u r s e it can be a r g u e d that t o l e r a n c e and d e p e n dence occur with non o p i o i d d r u g s as well, but such p h e n o m e n a are a prominent feature of o p i o i d s . Furthermore it is p o s s i b l e to suggest that such effects ( even in the c a s e of n o n o p i o i d s ) are mediated v i a an E O S f i n a l C o m m o n pathway. For these reasons a more detailed discussion of t h e s e p h e n o m e n a was d e e m e d n e c e s s a r y (see b e l o w ) . Nitrous o x i d e h a s a l s o b e e n u s e d as a s u b s t i t u t e for m o r p h i n e as a therapeutic agent, with benefit in a n u m b e r of c o n d i t i o n s including pain states, psychiatric illness(including withdrawal s t a t e s ) and in P a r k i n s o n ' s disease (14,21).
1212
Analgesic Nitrous Oxide and Opioid System
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The first direct evidence relating the analgesic effects of n i t r o u s o x i d e to the E O S w a s the d e m o n s t r a t i o n by B e r k o w i t z et al, that ~oth naloxone and n a l t r e x o n e attentuated nitrous oxide analg e s i a in m i c e (3). T h e y f u r t h e r showed that the a n a l g e s i c effects of n i t r o u s oxide c o u l d be s u p p r e s s e d by m o r p h i n e tolerance (3). These investigators also demonstrated that naloxone attenuated the nitrous oxide induced analgesia b u t n o t that p r o d u c e d by e t h a n o l or a s p i r i n tested on the phenylquinone abdominal constriction assay(22), Nitrous oxide analgesia as a s s e s s e d by the tail-flick test was also attenuated with naloxone in t h i s study(22). The tail-flick test has been shown to be an effective assay particularly of opioid produced analgesia (23). T h e s e analgesic (24,25) effects have been confirmed in o t h e r s t u d i e s . Tolerance .
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A further finding in the s t u d y by B e r k o w i t z et al, w a s t h a t a u t o tolerance could be produced in a n i m a l s by p r i o r exposure to nitrous oxide:a situation that is a n a l o g o u s to t o l e r a n c e produced by m o r p h i n e (22).This auto-tolerance effect has been confirmed by other investigators(26,27). It w a s a l s o s h o w n that this e f f e c t is p r o b a l ly s p e c i f i c since synaptic membrane fatty acid, phospholipid and cholesterol composition of t o l e r a n t mice brain extracts did not differ from non-tolerant controls (27). T h e p o s t u l a t e that nitrous oxide tolerance is a s p e c i f i c effect is f u r t h e r u n d e r l i n e d since mice tolerant to n i t r o u s o x i d e do n o t s h o w c r o s s tolerance to I arbiturates (28)~ Moreover an enkephalinase inhibitor(phosphoramidon) has been shown to p r e v e n t tolerance development to the a n a l g e s i c e~fects of n i t r o u s oxide;indicating that the EOS may become underactive during the development of tolerance to t h e g a s ( 1 0 ) . In a d d i t i o n acute dependence to t h e effects of n i t r o u s oxide in m i c e has also been demonstrated. Exposures of as l i t t l e as 30 m i n u t e s to 50% n i t r o u s oxide results in w i t h d r a w a l convulsions (29). F u r t h e r m o r e , Manson et al, h a s show~ that naloxone can precipitate an o p i o i d - l i k e withdrawal s t a t e in m i c e a f t e r a s i n g l e e x p o s u r e to 70% n i t r o u s o x i d e for 30 minutes (30). M o r e o v e r , these workers also demonstrated that this withdrawal response to n i t r o u s oxide was blunted if m o r p h i n e was given instead of naloxone. Other workers prior to this however,were unable to c a u s e a n a b s t i n e n c e syndrome with either naloxone or na Itrexone following exposure to t h e gas; and suggested t h a t the p h y s i c a l dependence on n i t r o u s oxide was more closely related to t h a t of e t h a n o l than morphine(31). This work however showed methadological differences, when compared to the otne~ study(30). Possibly the m o s t important of w h i c h were that the o p i o i d a n t a g o n i s t was given after removal of the a n i m a l s from the g a s exposure; and also higher concentrations and longer gas exposures were used (31). In addition tolerance and physical dependence may be d i s s o c i a t e d under certain conditions; for instance naloxone h a s f a i l e d to p r e c i p i t a t e a withdrawal sign when given to a h i g h l y tolerant vas de ferens preparat ions(32). Furthermore nitrous oxide can attenuate the m o r p h i n e abstinence
Vol. 39, No. 14, 1986
Analgesic Nitrous Oxide and Opioid System
1213
syndrome in r a t s ( 3 3 ) . E v i d e n c e has also been presented~in a study s t i l l to be c o n f i r m e d by o t h e r s , that rats tolerant to n i t r o u s o x i d e w e r e not t o l e r a n t to the a n a l g e s i c e f f e c t s of m o r p h i n e (34). This linding appears to be difficult to e x p l a i n however such unidirectional cross tolerance~ has b e e n o b s e r v e d to o c c u r b e t e e n m o r p h i n e and o t h e r o p i o i d s s u c h as h e r o i n and e t o r p h i n e ( 3 5 ) . Further evidence in f a v o u r of EOS i n v o l v e m e n t in the d e v e l o p m e n t of t o l e r a ~ c e and d e p e n d e n c e to n i t r o u s o x i d e ~ is the f i n d i n g that 18 h o u r s of e x p o s u r e to 7 5 - 8 0 % nitrous oxide resulted in a decrease of o p i o i d receptor density~ as m e a s u r e d at (3H) dihydromorphine b i n d i n g a s s a y s of rat b r a i n s t e m (36). F u r t h e r m o r e (3H)-raloxone binding is d e c r e a s e d a f t e r i h o u r of n i t r o u s oxide exposure in m i c e not resistant to the locomotor effects of morphine, whilst in c o n t r a s t ~ resistant mice did not show this e f f e c t (37). Locomotor .
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The locomotor stimulating effects of n i t r o u s oxide which are s i m i l a r to t h o s e p r o d u c e d by m o r p h i n e can a l s o be a t t e n u a t e d by both naltrexone and n a l o x o n e as w e l l as m o r p h i n e t o l e r a n c e (38). It m u s t be e m p h a s i z e d however, t h a t the a n a l g e s i c and locomotor effects of n i t r o u s oxide are different f r o m t h o s e of m o r p h i n e : highel c o n c e n t r a t i o n s of n a l o x o n e are r e q u i r e d to a n t a g o n i s e n i t ous o x i d e a n a l g e s i a , than are r e q u i r e d to reverse these effects of morphine (22). In a d d i t i o n , the l o c o m o t o r e f f e c t s of n i t r o u s o x i d e are not c o m p l e t e l y a b o l i s h e d by n a l o x o n e or n a l t r e x o n e (34). However this may indicate t h a t the g a s interacts with opioid receptors that are resistant to a n t a g o n i s m by these agents,such as kappa~ sigma or delta receptor s(39).Ano ther possibility is t h a t the g a s c a u s e s the r e l e a s e of e n d o g e n o u s o p i o i d p e p t i d e s ( s e e b e l o w ) w h i c h are m o r e r e s i s t a n t to a n t a g o n i s m by b l o c k i n g a g e n t s t h a n are e x o g e n o u s o p i o i d s ( 4 0 ) . Mice resistant to the l o c o m o t o r activity effects of m o r p h i n e have also been demor strated to be r e s i s t a n t to t h e s e e f f e c t s of n i t r o u s oxide (38). M o r e o v e r the c a t e c h o l a m i n e r g i c mechanisms that a p p e a r to be important in p r o d u c i n g the l o c o m o t o r e f f e c t s of b o t h m o r p h i n e and n i t r o u s o x i d e are s i m i l a r s i n c e these e f f e c t s are r e d u c e d by b o t h alpha-methyl-p-tyrosine and h a l o p e r i d o l administration(41). Release .
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Met-enkephalin but not leu-enkephalin l e v e l s h a v e b e e n s h o w n to be raised in t h e CSF of a n i m a l s exposed to n i t r o u s oxide (42)~however nitrous oxide exposure failed to c h a n g e metenke~ahalin l e v e l s in v a r i o u s b r a i n a r e a s in w o r k d o n e by o t h e r s (43). H o w e v e r , the l a t t e r finding could reflect no c h a n g e in stored neurotransmitter d e s p i t e long l a s t i n g r e l e a s e . T h i s idea is s u p p o r t e d by a n o t h e r a n i m a l s t u d y w h i c h has s h o w n that w h i l s t plasi~a b e t a - e n d o r p h i n levels were raised~ brain levels remained u n c h ~ n g e d d u r i n g n i t r o u s o x i d e e x p o s u r e (44). It is i n t e r e s t i n g to n o t e that in a h u m a n s t u d y n e i t h e r l e u - e n k e p h a i n or b e t a - e n d o r p h i n l e v e l s are r a i s e d in CSF d u r i n g n i t r o u s o x i d e a d m i n i s t r a t i o n (45). Unfortunately met-enkephalin l e v e l s w e r e not m e a s u r e d in the latter study. T h e s e c o n t r a d i c t o r y f i n d i n g s i n d i c a t e that f u r t h e r w o r k is n e c e s s a r y in this a r e a to c l a r i f y t h e s e i s s u e s .
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In v i t r o r a d i o - r e c e p t o r binding studies have demonstrated that nitrous oxide interferes with both 3(H)-dihydromorphine (46,47) and (3H)-naloxone binding(48)~ indicating that nitrous oxide interacts with the m u o p i o i d receptor as h a s b e e n p r e v i o u s l y suggested(49). Furthermore nitrous oxide produces a significant s h i f t in the IC50 v a l u e d e t e r m i n e d from (3)H-leuenkephalin binding experiments suggesting activity at the d e l t a binding s i t e as well(S7). These workers demonstrated that the gas had no e f f e c t on b i u d i n g at the k a p p a or s i g m a o p i o i d r e c e p t o r or at the G A B A site. The ligands used in this work were (3)He t h y ike t o c y c laz oc ine ,( 3 ) H - N - A I l y l - N - N o r m e t a z o c i n e ( S K F - l O , 0 4 7 ) and (3)H-~ u s c i m o l respectively (47). This data would appear to i n d i c a t e that the e f f e c t s of the gas are h i g h l y s p e c i f i c e v e n w i t h r e s p e c t to the o p i o i d r e c e p t o r . L a w r e n c e and L i v i n g s t o n , however w e r e u n a b l e to i n f l u e n c e (3H)- d i h y r o m o r p h i n e binding with nitrous oxide; h o w e v e r , it is not c l e a r h o w the n i t r o u s o x i d e w a s a p p l i e d to t h e i r a l i q u o t s . If t h e n i t r o u s o x i d e w a s s o l u b o l i z e d in o l i v e oil as seems likely Ifrom their description) this may have interfered with their results (25). F u r t h e r w o r k is s t i l l q u i t e c l e a r l y r e q u i r e d in this a r e a to c l a r i f y these d i s p a r a t e f i n d i n g s . Isolated .
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Isolated organ bath experiments i n v o l v i n g use of n i t r o u s o x i d e and gut preparations have provided negative results (Dreyer and Gillman, unpublished observations ; Ngai and Finck unpublished observations (36). T h e s e n e g a t i v e results are probably the m o s t serious f l a w in the h y p o t h e s i s that n i t r o u s o x i d e i n t e r a c t s w i t h opioid receptors,since i s o l a t e d o r g a n s are used as the c l a s s i c a l o p i o i d assay. H o w e v e r these n e g a t i v e f i n d i n g s are p r o b a b l y due to the practical difficulties of w o r k i n g with a gas in t h i s s i t u a t i o n . For i n s t a n c e n i t r o u s o x i d e is c o n s i d e r a b l y m o r e s o l u b l e than o x y g e n in b o t h w a t e r and lipids(50). T h i s w o u l d lead to r a p i d saturation of b o t h b u f f e r and and tissue within the o r g a n b a t h resulting in a n o x i a if the g a s e s are a p p l i e d at n o r m a l a n a l g e s i c conc~:ntrations(eg.50% nitrous oxide:50% o x y g e n ) . S u c h an a n o x i c p r e p a r a t i o n m i g h t c a u s e the o r g a n to b e c o m e t o t a l l y u n r e s p o n s i v e ; as w e f o u n d in o u r e x p e r i m e n t s ( D r e y e r and Gillman; unpublished observations) • In this r e g a r d it is n o t e w o r t h y that in e x p e r i m e n t s w i t h dogs that a n o x e m i c i r r e g u l a r c o n t r a c t i o n s of the gut w e r e o b s e r v e d f o l l o w i n g the a p p l i c a t i o n of a n e s t h e t i c c o n c e n t r a t i o n s of n i t r o u s oxide. If however a breath or t w o of o x y g e n w a s g i v e n t h e s e c o n t r a c t i o n s disappeared(51). Apart from the a n o x i c effect that may follow because of the solubility differences the rapid saturation of the organ by nitrous oxide within the bath could conceivably g i v e r i s e to rapid acute tolerance development; an e f f e c t that has b e e n s h o w n to occur with morphine within 3 minutes(52). It is d i f f i c u l t in v i e w of the f o r e g o i n g to v i s u a l i z e a m e t h o d of p r o v i d i n g a d e q u a t e
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Analgesic Nitrous Oxide and Opioid System
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levels of n i t r o u s oxide without running the r i s k s of p r o d u c i n g acute tolerance, w h i c h m a y be f o l l o w e d by anoxia. We are at the moment investigating the p o s s i b i l i t y of p r e v e n t i n g this rapid a c c u m l ~ l a t i o n of n i t r o u s o x i d e w i t h i n the p r e p a r a t i o n . An interesting finding that may also be significant is t h a t using infra-red spectroscopy nitrous oxide has been shown to attach to 2 d i s t i n c t sites; one polar and associated with the aqueo~is p h a s e a n d the o t h e r non-polar and linked to the l i p i d phase!53). T h i s m a y w e l l be s i g n i f i c a n t s i n c e it h a s b e e n suggeste~i t h a t the o p i o i d r e c e p t o r is c o m p o s e d of d i s t i n c t protein and lipid areas(54). HUMAN .
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The first p u b l i s h e d d e m o n s t r a t i o n in m a n that an a n a l g e s i c e f f e c t of n i t r o u s o x i d e c o u l d be r e v e r s e d by n a l o x o n e w a s t h a t in w h i c h the c e r e b r a l e v o k e d p o t e n t i a l to p a i n was used as the i n d i c a t o r of analgesia(55). S o o n a f t e r this, o t h e r w o r k e r s s h o w e d that low dose naloxone could attenuate nitrous oxide analgesia using acute experimental p a i n ( 5 6 , 5 7 ) as w e l l as c h r o n i c pain(49). In a n o t h e r study, using post-operative pain, the a n a l g e s i c response produced by n i t r o u s o x i d e c o u l d n o t be r e v e r s e d by n a l o x o n e ( 5 8 ) , however, these w o r k e r s f a i l e d to m a k e s u f f i c i e n t allowance for p h a r m a c o k i netic differences caused by the c o n t i n u o u s administration of nitrcus oxide and the extremely shor t half life of naloxone(59),since they assesed pain thresholds only after 40 minutes had e l a p s e d f r o m the time of n a l o x o n e a d m i n i s t r a t i o n ( 5 9 ) . It ha~ b e e n d e m o n s t r a t e d t h a t the c o n c e n t r a t i o n of n a l o x o n e in the C N S r i s e s r a p i d l y following i.v. b o l u s i n j e c t i o n ,but t h e s e l e v e l s are e v a n e s c e n t ( 6 0 ) . T h i s d o e s n o t a p p l y to m o r p h i n e where peak brain levels are reached more slowly but maintained much longel. These pharmacokinetics differences have b e e n u s e d to exp l a i n the p o t e n t but s h o r t - l i v e d morphine antagonistic e f f e c t of naloxone(61). Since nitrous oxide was given continuously during these e x p e r i m e n t s ( 5 8 ) it is p o s s i b l e that the a n t a g o n i s t i c effects of n a l o x o n e in this case c o u l d have b e e n e v e n s h o r t e r - a c t i n g than under normal circumstances(59). In the case of m o r p h i n e peak b r a i n l e v e l s o c c u r for up to 2 h o u r s , w h i l s t t h o s e of n a l o x o n e b e g i n to wane rapidly a f t e r a b o u t 15 m i n u t e s ( 6 0 ) . The i m p o r t a n c e of t h e s e pharmacokinetic diferrences appears to be b o r n e o u t by o u r f i n dingsin which the e f f e c t s of n a l o x o n e b e g a n to d i m i n i s h after 3 minutes disappearing completely within i0 m i n u t e s ; this during continuous analgesic nitrous oxide administration(56). It w o u l d thus a p p e a r that the c o n t r a d i c t o r y w o r k on c h r o n i c pain(58) o n l y "serves to c o n f u s e the i s s u e " ( 6 2 ) . A m o r e r e c e n t s t u d y in w h i c h naloxone(at low d o s e s ( l . 2 m g ) and i n j e c t e d s l o w l y over a 2-4 m i n u t e p e r i o d ) f a i l e d to r e v e r s e n i t r o u s o x i d e a n a l g e s i a of a n o c i c e p t i v e brain stem reflex also appears to s u f f e r from pharmacokinetic defects. In this w o r k the n e g a t i v e results were probably related to t h e i n a d e q u a t e d o s e s of a n t a g o n i s t used(63). This highlights the i m p o r t a n c e of u s i n g d o s e s of o p i o i d a n t a g o n i s t h i g h e n o u g h to effectively b l o c k all c l a s s e s of o p i o i d r e c e p t o r but at the s a m e t i m e not h i g h e n o u g h so that that s p e c i f i c i t y for these r e c e p t o r s is lost.
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Haugen et al (64) d e m o n s t r a t e d that the analgesia produced by nitrous oxide during painful tooth stimulation (at the same concentrations) decreased after a number of experimental runs. These workers suggested that this effect was caused by l e a r n i n g . H o w e v ~ r~ s o m e of t h e s e e x p e r i m e n t a l runs occurred a f t e r o n l y a IO minute rest period~ and it is t h e r e f o r e possible, and even likely that these results were a manifestation of a c u t e t o l e r a n c e to the gas. f u r t h e r m o r e , other workers(65) have also demonstrated acute tolerEnce to the a n a l g e s i c effects of n i t r o u s oxide, inasmuch as contiruous administration of 33% n i t r o u s o x i d e for I h o u r r e s u l t e d in p a i n t h r e s h o l d s being t h e s a m e at t h e b e g i n n i n g of as at t h e e n d of t h e e x p e r i m e n t in s o m e subjects. However, these workers w e r e ~ b l e to p r e v e n t the d e v e l o p m e n t of this a c u t e t o l e r a n c e if a 50% concentration of n i t r o u s oxide was arrived at b y g r a d u a l increnents o v e r a 45 m i n u t e period. If t h e s e g r a d u a l increments were used, the effect of n i t r o u s oxide w a s to i n c r e a s e the pain threshold twofold. This implies that a c u t e t o l e r a n c e to a s i n g l e concentration of nitrous oxide can occur within an hour. Abuse .
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Oxide
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Although many paradigms have been devised to s h o w t h a t s e l f a d ministration of morphine in a n i m a l s is s u g g e s t i v e of abuse potential~ only recently have such experiments b e e n u s e d in the c a s e of nitrous oxide. W o o d et a i ( 6 6 ) h a v e c l e a r l y demonstrated such behaviour in the s q u i r r e l monkey. The human abuse potential of n i t r o u s oxide has been known ever since the euphoriant effects of t h e g a s w a s first described by Davy. In a d d i t i o n , a s t u d y by R o s e n b e r g et al i n v o l v i n g 524 m e d i cal and dental students who responded to a q u e s t i o n a i r e indicated t h a t 20% of t h e s e s t u d e n t s had utilised n i t r o u s o x i d e at s o m e t i m e to o b t a i n "a h i g h " ( 6 7 ) . Therapeutic .
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Kripke and Hechtman(68) described a c a s e of p e n t a z o c i n e addiction whic~ was successfully treated with analgesic concentrations of nitrous oxide; further demonstrating that nitrous o x i d e is c a p a b l e of being u s e d as a substitute for a known opioid agent in t h e treatment of a w i t h d r a w a l state. G i l l m a n and Lichtigfeld (69) h a v e successfully treated 2 c a s e s of o p i o i d addiction and withdrawal usin~ analgesic nitrous oxide. It t h u s a p p e a r s that nitrous oxide may prove to be a u s e f u l tool for the treatment of o p i a t e withdrawal states(70)~ which merits further investigation.
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A C T I O N OF A N A L G E S I C W I T H THE E O S
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There has been some debate not only regarding the possibility nitrous oxide interacts w i t h the E O S b u t a l s o w h e t h e r this occurs directly (as a n a g o n i s t on opioid receptors) as proposed by Gillman and Lichtigfeld(49,59,71) or i n d i r e c t l y as postulated by
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Analgesic Nitrous Oxide and Opioid System
1217
others that these effects of n i t r o u s oxide are mediated via release of e n d o g e n o u s opioids (22~36,38,42). These ideas h o w e v e r are not m u t u a l l y exclusive, since it is p o s s i b l e that b o t h m e c h a nisms m a y be i n v o l v e d , as has been s h o w n to o c c u r in the case of morphine (72). The e x a c t m e c h a n i s m of a c t i o n of n i t r o u s o x i d e at the o ~ i o i d receptor c a n n o t at p r e s e n t be f i n a l l y described, but this author (73) h a s suggested 3 possible mechanisms. First n i t r o u s o x i d e c o u l d act d i r e c t l y as an a g o n i s t in a m a n n e r a n a l a gous to that of t e t r a m e t h y l - a m m o n i u m , which although a very small molecule is a n i c o t i n i c agonist. Second,itis possible that the Nitrogen and Oxygen (which appeared to be k e y a t o m s for o p i o i d activity) of 2 d i f f e r e n t nitrous oxide molecules might lock simulultaneously into the 2 key a r e a s on the o p i o i d r e c e p t o r , thus producing its o p i o i d effects. The work of C a u g h e y et al (53) demonstrating the d i s t r i b u t i o n of n i t r o u s o x i d e in b o t h the lipid and a q u e o u s p h a s e s u p p o r t this c o n c e p t and w o u l d a c c o r d w i t h the known chemistry of N i t r o g e n and Oxygen. Third, a non specific e f f e c t at the r e c e p t o r such as o x i d a t i o n , may activate the o p i o i d receptor (see ref 73for d e t a i l s of t h e s e mechanisms). It is also p o s s i b l e to p o s t u l a t e that n i t r o u s o x i d e m a y act as a partial agonist (competitive dualist). Maruyama et al (74) u s i n g the e l e c t r o - s p i n o g r a m w e r e able to d e m o n s t r a t e that n i t r o u s o x i d e tended to r e d u c e the e f f e c t s of m o r p h i n e in t h e i r e x p e r i m e n t s . Furthermore, ketamine analgesia has b e e n s h o w n to act via o p i a t e receptors (75), a n d a n e s t h e t i c requirements of k e t a m i n e are red u c e d in the p r e s e n c e of n i t r o u s o x i d e (76).This indicates, that ketamine and nitrous oxide may act synergistically at the opioid receptor(14). In v i e w of t h e s e f i n d i n g s nitrous oxide may a c t as a p a r t i a l agonist ( or c o m p e t i t i v e dualist) at the o p i o i d receptor(14). In t h i s r e s p e c t it is s i m i l a r to p e n t a z o c i n e which is a l ~ o a p a r t i a l agonist (77). It is t h e r e f o r e significant that n i t r o u s o x i d e has b e e n used to ameliorate the a b s t i n e n c e s y n d r o m e caused by a p e n t a z o c i n e addiction (68). S i n c e p e n t a z o c i n e is an a g o n i s t at the k a p p a r e c e p t o r (77), it is c o n c e i v a b l e that n i t r o u s oxide may also have activity at t h i s as w e l l as the m u r e c e p t o r . Further evidence indicating that n i t r o u s o x i d e i n t e r a c t s w i t h the k a p p a r e c e p t o r is p r o v i d e d by H y m e s and H y m s o n w h o h a v e s h o w n that nitrous oxide generalizes to a d i s c r i m i n a t i v e s t i m u l u s p r o v i d e d by ethylketocyclazocine which is a kappa agonist but not morphine(78).The fact that high doses of n a l o x o n e are required to antagonise n i t r o u s o x i d e a n a l g e s i a than are r e q u i r e d to a n t a g o n i s e that of m o r p h i n e adds further support to the postulate that nitrous oxide is a k a p p a agonist or c a u s e s the r e l e a s e of the endog~ nous l i g a n d for the k a p p a r e c e p t o r , s i n c e b o t h mu and k a p p a receptors appear to be i n v o l v e d in o p i o i d analgesia(79); and naloxone has much less affinity for the k a p p a t h a n for the mu receptor (39). Thus one would expect it to require higher concentrations of n a l o x o n e to block kappa receptor effects initiated by n i t r o u s oxide. Furthermore~ since neither naloxone nor naltrexone can entirely abolish the locomotor effects of nitrous oxide(38) this m i g h t i n d i c a t e a n o t h e r r e c e p t o r a p a r t f r o m the m u r e c e p t o r is i n v o l v e d in m e d i a t i n g p a r t of t h e s e e f f e c t s . This is in a g r e e m e n t w i t h the f i n d i n g s of l w a m o t a , w h o has s h o w n that both the m u and sigma receptor are involved in o p i o i d p r o d u c e d l o c o m o t o r a c t i v i t y (79). M o r e o v e r the s i g m a r e c e p t o r can under certain conditions be r e s i s t a n t to n a l o x o n e and n a l t r e x o n e blockade (80). If n i t r o u s oxide is a c t i v e via sigma mediated mechanisms as w e l l this m a y e x p l a i n the i n a b i l i t y of n a l o x o n e to
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Analgesic Nitrous Oxide and Opioid System
e te ly
block
the
locomotor
Vol. 39, No. 14, 1986
e f fect
s
of
the
gas.
CONCLUSIONS .
Of the 5 criteria suggested by S a w y n o k et a l ( ~ l ) t o be to s a t i s f y the r e q u i r e m e n t s for d e f i n i t i o n as an o p i o i d h a v e b e e n m e t viz : i)
the
demonstration
2)
evidence
3)
other opioid antagonists s a n e e f f e c t s as n a l o x o n e .
for
the
of
cross-tolerance
direct
release (in
of
this
necessary agonist 3
to m o r p h i n e . opioid case
peptides.
naltrexone)
produce
the
In a d d i t i o n in v i t r o binding studies (46,47,48) add further e v i d e n c e for the h y p o t h e s i s that some of the e f f e c t s of a n a l g e s i c n i t r o r s o x i d e are m e d i a t e d via an i n t e r a c t i o n w i t h the EOS. T h e s e latter data according to H u g h e s and K o s t e r l i t z provides final confirmation of of an agents interaction with opioid receptors(81). Therefore it w o u l d appear that 3 more criteria n e e d I o be m e t b e f o r e the h y p o t h e s i s that a n a l g e s i c n i t r o u s o x i d e inter~ cts w i t h o p i o i d r e c e p t o r s is f i n a l l y proven~ n a m e l y : I)
It m u s t p r o d u c e a dose of m o u s e vas d e f e r e n s , pig i l e u m ( 7 8 ) .
2)
The agonist fic(ll,78).
3)Agents that potentiate
and
related inhibition cat n i c t i t a t i n g
antagonist
effects
of n e r v e membrane
must
be
contractions and g u i n e a -
stereospeci-
i n h i b i t the b r e a k d o w n of e n d o g e n o u s opioids the n a l o x o n e antagonised response(ll).
also
In c o n c l u s i o n ~ a l t h o u g h e v i d e n c e is still l a c k i n g and s o m e i m p o r tant investigations must s t i l l be u n d e r t a k e n there is a l r e a d y considerable experimental support for the c o n c e p t that analgesic nitrous oxide interacts with the E O S to p r o d u c e some of its pharmacological effects. Furthermore, it is p o s s i b l e to s p e c u l a t e that nitrous oxide interacts directly and/or indirectly(i.e.by r e l e s s i n g e n d o g e n o u s o p i o i d s ) not only w i t h the mu, but w i t h o t h e r opioid receptors v i z . t h e d e l t a , k a p p a and s i g m a r e c e p t o r s . This non s p e c i f i c i t y in r e l a t i o n to o p i o i d r e c e p t o r s m a y be c o n s i s t a n t with the p o s s i b i l i t y that nitrous oxide was conceivably the primordial opioid substance(82,83). Acknowledgements
Part of t h i s work was presented by the a u t h o r in the T h e s i s "NITROUS OXIDE AS AN O P I O I D AGONIST : SOME EXPERIMENTAL AND CLINICAL APPLICATIONS". presented in fulfilment of the requirements for the d e g r e e D.Sc. at P o t c h e f s t r o o m University, South Africa. S u p p o r t e d by a g r a n t from A n g l o - A m e r i c a n and De B e e r s C o r p o r a t i o n of S o u t h Africa. Mrs M a r t h a O p p e n h e i m is t h a n k e d for s k i l l f u l p r o o f - r e a d i n g .
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