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Depressive effects of morphine and of an enkephalinase inhibitor on responses of ventro-basal thalamic neurones to noxious stimuli
Life Sciences, Vol. 33, Sup. I, 1983, pp. 545-547 Printed in the U.S.A.
Pergamon Press
DEPRESSIVE EFFECTS OF HORPHINE AND OF AN ENKEPHALINASE INHIBITOR RESPONSES OF VENTRO-BASAL THALAHIC NEURONES TO NOXIOUS STIMULI.
ON
G. Guilbaud, V. Kayser, J.M. Benoist and M. Gautron. Unit@ 151 INSERH, 2 rue d'A16sia 75015 Paris (France). (Received in final form June 26, 1983)
St~ar~ I t has been shown t h a t t h e reponses o f VB t h a l a m i c neurones t o noxious mechanical and thermal s t i m u l i are s t r o n g l y depressed by low doses o f Morphine (0,05 ; 0,1 ; i mg/kg i . v . ) and to a l e s s e r e x t e n t by ES 52 (a h i g h l y potent Thiorphan d e r i v a t i v e ) i n j e c t e d at higher doses (5 ; i0 mg/kg i ° v ) . This l a s t e f f e c t was less e a s i l y reversed by Naloxone than was the depressive e f f e c t o# Morphine° Moreover, ES 52 can f a c i l i t a t e a c t i v i t y o f some t h a l a m i c neurones induced by non-noxious mechanical s t i m u l i ° (Introduction) We have p r e v i o u s l y described (3) numerous neurones e x c l u s i v e l y d r i v e n by noxious s t i m u l i (N neurones), as w e l l as a s ma lle r p o p u l a t i o n d r i v e n by both noxious and non-noxious s t i m u l i (NNn neurones), i n the VB complex o f the r a t . I t has a l s o been shown (7) t h a t N neurones were able to encode s e v e r a l parameters o f a noxious thermal s t imu lu s . We have thus considered the e f f e c t o f Morphine on response o f such t h a l a m i c neurones to noxious s t i m u l i ; we then evaluated e f f e c t s o f a potent Thiorphan d e r i v a t i v e (ES 52) an enkephalinase i n h i b i t o r , a l r e a d y described by Roques and a l (8) and repprted to have a n a l g e s i c p r o p e r t i e s ( 2 , 8 ) ° Behavioural s t udies have shown t h a t both Morphine and ES 52 doses used were e f f e c t i v e l y a n a l g e s i c ( 5 ) .
Methods Recording were c a r r i e d out i n Sprague Dawley r a t s weighing 220-270g under c o n d i t i o n s described p r e v i o u s l y ( 3 ) . B r i e f l y u n i t recordings were p e r f o r m e d under gazeous a n a e s t h e s i a (NpO 2/3 02 1/3 h a l o t h a n e 0.5%) c o n t i n o u s l y monitored by an electrocorUicogram ; pontamine sky blue contained i n the m i c r o e l e c t r o d e s allowed the l o c a l i z a t i o n o f each r e c or ding site. Neurones were characterized as previously reported (3) in terms of response to mechanical stimuli and classified as "nociceptive" (N) for those driven by noxious stimuli (pinches) or "convergent" (NNn) for those driven by both noxious and non-noxious (light touch, brushing) stimuli. In most cases only one dose of the drug studied was tested on one neurone in one rat. Effects were analysed upon reproducible responses induced by a constant stimulation of 15 sec duration applied every 5 minutes and elicited by a graduated forceps or a hot water bath of 50 °. Effects of Morphine (0,03 ; 0,I ; I mg/kg i.v.) were tested on responses of N neurones to pinch (18 cases) and/or to noxious heat (I0 0024-3205/83 $3.00 + .00 Copyright (c) 1983 Pergamon Press Ltd.
546
Morphine and VB Thalamic Neurones
Vol. 33, Sup. I, 1983
c a s e s ) , f h o s e o f ES 52 (5 ; 10 mg/kg i . v . ) were t e s t e d on r e s p o n s e s o f N n e u r o n e s t o p i n c h (13 c a s e s ) , and a l t e r n a t e l y , t o n o x i o u s h e a t (12 c a s e s ) . This compound (5 mg/kg) was a l s o t e s t e d on r e s p o n s e s o f NNn n e u r o n e s t o p i n c h and t o l i g h t touch (]0 cases), alternately, t o n o x i o u s h e a t (S cases). F o r each n e u r o n e , t h e number o f s p i k e s i n each t e s t r e s p o n s e was counted, including the after-discharge characteristic o f t h e N and NNn n e u r o n e s . These d a t a were t h e n e x p r e s s e d as a p e r c e n t a g e o f c o n t r o l v a l u e ; mean d e p r e s s i v e e f f e c t was e v a l u a t e d f o r each d o s e .
Results A) There was a d e c r e a s e o f t h e t o t a l number o f s p i k e s p e r r e s p o n s e i n t h e N n e u r o n e s w i t h a l l H o r p h i n e doses used i n t h i s s t u d y . 15 to 20 min after injection, the mean responses to pinches were depressed by 30, 50, 92% for respectively 0,03 ; 0,i ; i mg/kg. This depressive effect was significantly dose-related (with linear semi-logarithmic dose-response curve) and naloxone reversible (with a dose equivalent to the 1/10th of the dose of morphine injected 20 min later). The dose reducing response levels by 50% was approximately to 0,09 mo/kg, Similar effects were o b s e r v e d upon r e s p o n s e s t o noxious heat, B) -A dose o f 5 mg/kg o f ES 52 i n d u c e d a s i g n i f i c a n t decrease in the number o f s p i k e s i n t h e mean r e s p o n s e o f N n e u r o n e s t o p i n c h and t o n o x i o u s heat, (by 56% 15 minutes after the injection). The d e p r e s s i v e effect observed for the neurones tested with i0 mg/kg was not s i g n i f i c a n t l y different. Naloxone injected at the dose of 0,5 mg/kg, 20 minutes after ES 52, reversed the depressive effect in only half of the cases.
-With ES 52 (5 mg/kg) the mean response of NNn neurones to noxious heat was depressed by 42% 15 min after the injection. Response of these neurones to pinch were apparently u n modified ; however there was a procounced enlargement of the receptor field to non noxious stimuli which could mask a possible decrease in neuronal response to the noxious mechanical stimuli. - I n 3 cases t h e e f f e c t o f m o r p h i n e (1 mg/kg i . v . ) was t e s t e d on r e s p o n s e o f t h e s e NNn n e u r o n e s t o p i n c h o r t o n o x i o u s h e a t , 15 and 20 m i n u t e s a f t e r ES 52 a d m i n i s t r a t i o n . The r e s p o n s e o f t h e s e n e u r o n e s t o b o t h s t i m u l i was s t r o n g l y d e p r e s s e d by m o r p h i n e , t h i s e f f e c t was n a l o x o n e - r e v e r s i b l e (O,1 m g / k g ) .
Conclusion The depressive action of morphine upon neuronal VB responses to noxious stimuli is much more pronounced than that reported for spinal dorsal horn neurones in this species (6). Therefore the depressive effect of these low doses in thalamic neurones seems to be mainly of supraspinal origin, fhis observation, discussed elsewhere (1), is in good agreement with a recent study of Hill et al. (4) reporting that neuronal response to noxious stimuli recorded in the trigeminal system was less sensitive to morphine than that recorded at the thalamic level. In any case, these data enhanced the funtional significance of these VB N neurones, since the same low doses of Morphine have a n a l g e s i c s
Vol. 33, Sup. I, 1983
Morphine and VB Thalamic Neurones
p r o p e r t i e s (5)° The depressive e f f e c t of ES 52 on responses to noxious s t i m u l i seems t o provide some e l e c t r o p h y s i o l o g i c a l basis f o r the a n a l g e s i c a c t i o n d e s c r i b e d w i t h t h i s compound (5) and w i t h f h i o r p h a n ( 2 , 8 ) . Nevertheless, i t should be noted t h a t t h i s depressive e f f e c t i s less e a s i l y reversed by naloxone than t h a t of morphine. fhe f a c t t h a t ES 52 can enhance response to non-noxious mechanical s t i m u l i f u r t h e r i l l u s t r a t e s the complexity o f the endomorphinic systems°
References
1° 3°H. Benoist, Vo Kayser, M. Gautron and G. Gui]baud Pain ]5, 333-3~4 (1983). 2. S° De l a Baume, C.C Y i , J.C. Schwartz, P. C h a i l l e t , and J° C o s t e n t i n . Neurosc. 8, 143-151 (1983).
H. Harcois Collado
3. C° Guilbaud, M. Peschanski, M. Gautron and O. Binder. Pain 8, 303-318 (1980). 4° R.G. H i l l , T.E. S a l t and C°M. Pepper L i f e Sc. 31, 2331-2334 (1982). 5. V° Kayser, G. Guilbaud 8 r a i n Research 267, 131-138 (1983). 6° O. Le Bars, G. Guilbaud, D. Chitour and J.M° 3esson Brain Research 202, 223-228 (1980). 7. M. Peschanski, G. Guitbaud, M. Gautron and J.H. Besson 8 r a i n Research 197, 401-413 (1980)° 8. B.P. Roques, M.C. F o u r n i e - Z a l u s k i , M a l f r o y , C. L l o r e n s , J.C° Schwartz Nature (Lond) 288, 286-288 (1980).
E.S.
Sorola,
J.M°
Lecomte, B.
547
Pergamon Press
DEPRESSIVE EFFECTS OF HORPHINE AND OF AN ENKEPHALINASE INHIBITOR RESPONSES OF VENTRO-BASAL THALAHIC NEURONES TO NOXIOUS STIMULI.
ON
G. Guilbaud, V. Kayser, J.M. Benoist and M. Gautron. Unit@ 151 INSERH, 2 rue d'A16sia 75015 Paris (France). (Received in final form June 26, 1983)
St~ar~ I t has been shown t h a t t h e reponses o f VB t h a l a m i c neurones t o noxious mechanical and thermal s t i m u l i are s t r o n g l y depressed by low doses o f Morphine (0,05 ; 0,1 ; i mg/kg i . v . ) and to a l e s s e r e x t e n t by ES 52 (a h i g h l y potent Thiorphan d e r i v a t i v e ) i n j e c t e d at higher doses (5 ; i0 mg/kg i ° v ) . This l a s t e f f e c t was less e a s i l y reversed by Naloxone than was the depressive e f f e c t o# Morphine° Moreover, ES 52 can f a c i l i t a t e a c t i v i t y o f some t h a l a m i c neurones induced by non-noxious mechanical s t i m u l i ° (Introduction) We have p r e v i o u s l y described (3) numerous neurones e x c l u s i v e l y d r i v e n by noxious s t i m u l i (N neurones), as w e l l as a s ma lle r p o p u l a t i o n d r i v e n by both noxious and non-noxious s t i m u l i (NNn neurones), i n the VB complex o f the r a t . I t has a l s o been shown (7) t h a t N neurones were able to encode s e v e r a l parameters o f a noxious thermal s t imu lu s . We have thus considered the e f f e c t o f Morphine on response o f such t h a l a m i c neurones to noxious s t i m u l i ; we then evaluated e f f e c t s o f a potent Thiorphan d e r i v a t i v e (ES 52) an enkephalinase i n h i b i t o r , a l r e a d y described by Roques and a l (8) and repprted to have a n a l g e s i c p r o p e r t i e s ( 2 , 8 ) ° Behavioural s t udies have shown t h a t both Morphine and ES 52 doses used were e f f e c t i v e l y a n a l g e s i c ( 5 ) .
Methods Recording were c a r r i e d out i n Sprague Dawley r a t s weighing 220-270g under c o n d i t i o n s described p r e v i o u s l y ( 3 ) . B r i e f l y u n i t recordings were p e r f o r m e d under gazeous a n a e s t h e s i a (NpO 2/3 02 1/3 h a l o t h a n e 0.5%) c o n t i n o u s l y monitored by an electrocorUicogram ; pontamine sky blue contained i n the m i c r o e l e c t r o d e s allowed the l o c a l i z a t i o n o f each r e c or ding site. Neurones were characterized as previously reported (3) in terms of response to mechanical stimuli and classified as "nociceptive" (N) for those driven by noxious stimuli (pinches) or "convergent" (NNn) for those driven by both noxious and non-noxious (light touch, brushing) stimuli. In most cases only one dose of the drug studied was tested on one neurone in one rat. Effects were analysed upon reproducible responses induced by a constant stimulation of 15 sec duration applied every 5 minutes and elicited by a graduated forceps or a hot water bath of 50 °. Effects of Morphine (0,03 ; 0,I ; I mg/kg i.v.) were tested on responses of N neurones to pinch (18 cases) and/or to noxious heat (I0 0024-3205/83 $3.00 + .00 Copyright (c) 1983 Pergamon Press Ltd.
546
Morphine and VB Thalamic Neurones
Vol. 33, Sup. I, 1983
c a s e s ) , f h o s e o f ES 52 (5 ; 10 mg/kg i . v . ) were t e s t e d on r e s p o n s e s o f N n e u r o n e s t o p i n c h (13 c a s e s ) , and a l t e r n a t e l y , t o n o x i o u s h e a t (12 c a s e s ) . This compound (5 mg/kg) was a l s o t e s t e d on r e s p o n s e s o f NNn n e u r o n e s t o p i n c h and t o l i g h t touch (]0 cases), alternately, t o n o x i o u s h e a t (S cases). F o r each n e u r o n e , t h e number o f s p i k e s i n each t e s t r e s p o n s e was counted, including the after-discharge characteristic o f t h e N and NNn n e u r o n e s . These d a t a were t h e n e x p r e s s e d as a p e r c e n t a g e o f c o n t r o l v a l u e ; mean d e p r e s s i v e e f f e c t was e v a l u a t e d f o r each d o s e .
Results A) There was a d e c r e a s e o f t h e t o t a l number o f s p i k e s p e r r e s p o n s e i n t h e N n e u r o n e s w i t h a l l H o r p h i n e doses used i n t h i s s t u d y . 15 to 20 min after injection, the mean responses to pinches were depressed by 30, 50, 92% for respectively 0,03 ; 0,i ; i mg/kg. This depressive effect was significantly dose-related (with linear semi-logarithmic dose-response curve) and naloxone reversible (with a dose equivalent to the 1/10th of the dose of morphine injected 20 min later). The dose reducing response levels by 50% was approximately to 0,09 mo/kg, Similar effects were o b s e r v e d upon r e s p o n s e s t o noxious heat, B) -A dose o f 5 mg/kg o f ES 52 i n d u c e d a s i g n i f i c a n t decrease in the number o f s p i k e s i n t h e mean r e s p o n s e o f N n e u r o n e s t o p i n c h and t o n o x i o u s heat, (by 56% 15 minutes after the injection). The d e p r e s s i v e effect observed for the neurones tested with i0 mg/kg was not s i g n i f i c a n t l y different. Naloxone injected at the dose of 0,5 mg/kg, 20 minutes after ES 52, reversed the depressive effect in only half of the cases.
-With ES 52 (5 mg/kg) the mean response of NNn neurones to noxious heat was depressed by 42% 15 min after the injection. Response of these neurones to pinch were apparently u n modified ; however there was a procounced enlargement of the receptor field to non noxious stimuli which could mask a possible decrease in neuronal response to the noxious mechanical stimuli. - I n 3 cases t h e e f f e c t o f m o r p h i n e (1 mg/kg i . v . ) was t e s t e d on r e s p o n s e o f t h e s e NNn n e u r o n e s t o p i n c h o r t o n o x i o u s h e a t , 15 and 20 m i n u t e s a f t e r ES 52 a d m i n i s t r a t i o n . The r e s p o n s e o f t h e s e n e u r o n e s t o b o t h s t i m u l i was s t r o n g l y d e p r e s s e d by m o r p h i n e , t h i s e f f e c t was n a l o x o n e - r e v e r s i b l e (O,1 m g / k g ) .
Conclusion The depressive action of morphine upon neuronal VB responses to noxious stimuli is much more pronounced than that reported for spinal dorsal horn neurones in this species (6). Therefore the depressive effect of these low doses in thalamic neurones seems to be mainly of supraspinal origin, fhis observation, discussed elsewhere (1), is in good agreement with a recent study of Hill et al. (4) reporting that neuronal response to noxious stimuli recorded in the trigeminal system was less sensitive to morphine than that recorded at the thalamic level. In any case, these data enhanced the funtional significance of these VB N neurones, since the same low doses of Morphine have a n a l g e s i c s
Vol. 33, Sup. I, 1983
Morphine and VB Thalamic Neurones
p r o p e r t i e s (5)° The depressive e f f e c t of ES 52 on responses to noxious s t i m u l i seems t o provide some e l e c t r o p h y s i o l o g i c a l basis f o r the a n a l g e s i c a c t i o n d e s c r i b e d w i t h t h i s compound (5) and w i t h f h i o r p h a n ( 2 , 8 ) . Nevertheless, i t should be noted t h a t t h i s depressive e f f e c t i s less e a s i l y reversed by naloxone than t h a t of morphine. fhe f a c t t h a t ES 52 can enhance response to non-noxious mechanical s t i m u l i f u r t h e r i l l u s t r a t e s the complexity o f the endomorphinic systems°
References
1° 3°H. Benoist, Vo Kayser, M. Gautron and G. Gui]baud Pain ]5, 333-3~4 (1983). 2. S° De l a Baume, C.C Y i , J.C. Schwartz, P. C h a i l l e t , and J° C o s t e n t i n . Neurosc. 8, 143-151 (1983).
H. Harcois Collado
3. C° Guilbaud, M. Peschanski, M. Gautron and O. Binder. Pain 8, 303-318 (1980). 4° R.G. H i l l , T.E. S a l t and C°M. Pepper L i f e Sc. 31, 2331-2334 (1982). 5. V° Kayser, G. Guilbaud 8 r a i n Research 267, 131-138 (1983). 6° O. Le Bars, G. Guilbaud, D. Chitour and J.M° 3esson Brain Research 202, 223-228 (1980). 7. M. Peschanski, G. Guitbaud, M. Gautron and J.H. Besson 8 r a i n Research 197, 401-413 (1980)° 8. B.P. Roques, M.C. F o u r n i e - Z a l u s k i , M a l f r o y , C. L l o r e n s , J.C° Schwartz Nature (Lond) 288, 286-288 (1980).
E.S.
Sorola,
J.M°
Lecomte, B.
547