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Antinociceptive interaction between alprazolam and opioids: Genetic differences
223
ANTINOCICEPTIVE INTERACTION BETWEEN ALPRAZOLAM A N D OPIOIDS: GENETIC DIFFERENCES. Chaim G. Pick, Dept. of Anatomy and Anthropology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978 Israel. This s t u d y was designed to investigate the antinociceptive effects of one of the most prescribed benzodiazepines i.e. alprazolam. Groups of CD-1, BALB/c, C57BL a n d Swiss mice were treated with alprazolam, a d m i n i s t r a t e d alone or in c o m b i n a t i o n with morphine. Analgesia was assayed, using the r a d i a n t heat tailflick. Alprazolam (1 mg/kg, i.p.) elicited analgesia in BALB/c mice with an ED50 value of 1.1 m g / k g . No analgesia was observed in CD-1 or C57BL mice. The s e n s i t i v i t y of Swiss mice was weak. l n t r a t h e c a l a d m i n i s t r a t i o n o f alprazolam elicited analgesia in a d o s e - d e p e n d e n t m a n n e r in the BALB/c, Swiss a n d CD-1 mice. C57BL mice were completely inactive in the tailflick test after alprazolam injection. I n t r a c e r e b r o v e n t r i c u l a r a d m i n i s t r a t i o n elicit only very weak analgesia in the BALB/c mice. We f o u n d a synergistic increase in analgesia when a subthreshold dose of alprazolam was given with m o r p h i n e in the BALB/c mice. This interaction was antagonized by naloxone, indicating that at least some of the analgesic effects of alprazolam are m e d i a t e d by an opioid mechanism of action. No effect was found when alprazolam was coadministrated with o t h e r specific opioid agonists. Our results d e m o n s t r a t e that injections of alprazolam can produce analgesia u n d e r different genetic controls a n d modify morphine-induced antinociception in mice as assessed in the tailflick assay. Male CD-1, CFW(SW)BR (Swiss), C57BL/J6 (C57BL) a n d BALB/cAmNCrIBR (BALB/c) were uesed. Analgesia was determined, using the radiant heat tailflick technique as previously described( 1 ). Dose-response curves were analyzed, using a SPSS c o m p u t e r program and single-dose studies were analyzed, using the Fisher exact test. Following an i.p. injection, alprazolam elicited analgesia in a d o s e - d e p e n d e n t m a n n e r in BALB/c mice with ED50 value of 1.1 mg/kg. The Swiss mice were almost inactive a n d CD-1 a n d C57BL mice were completely inactive. Intrathecal administration of alprazolam elicited analgesia in a dosed e p e n d e n t m a n n e r in the BALB/c Swiss, and CD-1 mice. ED50 values were 10~g ,22.8~g and 34.6~tg, respectively. C57BL mice were completely inactive in the tailflick test after alprazolam injection. Intracerebroventricular administration did not elicit analgesia more than 13% (after 50 ~g in the BALB/c mice). In a separate tail-flick assay with BALB/c mice, alprazolam (2.5 mg/kg) p r o d u c e d analgesia in 70°,4 of the mice. Naloxone ( 1 mg/kg) abolished almost completely the analgesia response ( P< 0.05). Coadministration of alprazolam (0.1 mg/kg) with m o r p h i n e (1.0 m g / k g ) elicited analgesia in 70% of the BALB/c mice, naloxone (1 mg/kg) a n t a g o n i z e d this analgesia almost completely (P< 0.05). Next we assessed in the BALB/c mice the simultaneous a d m i n i s t r a t i o n of the selective agonists of ~, 8 and K1 receptor subtypes and alprazolam to evaluate the potential synergism between a l p r a z o l a m a n d opioid analgesia. When m o r p h i n e (Fig. 1) was coadministrated with alprazolam, we found a 5-fold shift to the left: The ED50 of m o r p h i n e without alprazolam was 3.2 m g / k g and with a l p r a z o l a m was 0.5 m g / k g . In c o n t r a s t to o u r findings with m o r p h i n e , no
224
synergism was fotmd or wllh [15(),4881 I.
when a fixed close of aiprazolam was given with DPDPE Morphine dose response curve with and without alprazolam.
I009080-
~"
70-
~
60-
"~
40-
/
Moq~hh~ ( rag&g,s.c.)
Mo~hine( mg/kg, s.c.) + Alpr~olmn (01• ,''
/
/
3020-
100.1
i
;0
Morphine Dose (mg/kg)
Alprazolam is known lo have a unique clinical spectrum among the high potent beHzodiazepim_'s. Clinical o b s e r v a t i o n s suggest that in some types of pain s y n d r o m e s , specifically Ihose inw}lvlng nerve injuries, alprazolam m a y be ttselul as an adjuHc! to narcotic analgesia for pain control (2). Like most n e u r o t r a u s m l t t e r s , tim opiates and opioid p e p t i d e s interact with multiple classes of receplors. Each sul)class has its UnklUe profile of ligand selectivity, regi(mal d i s l r i b u t l o n and pharmacological actions a n d each is c a p a b l e of moduhtlh~g the perceplJoH oJ pain. Classically, t~ receptors have been implicated in opiale analgesia, btml recent works indicate tim ability of a n u m b e r of opiold r e c e p l o r s y s t e m s Io elhi! analgesia l n d e p e n d e n l l y . I)I'I)PE have clearly d e m o n s t r a l e d ~3analgesic mechanisms. A highly KI-seleclive agonist U50,488 elhils seleclive KI analgesia arid naloxone b e n z o y l h y d r a z o n e (NalBzoll) has beeH a uselul tool in examJniHg ~3 analgesia (3). Tim d a t a p r e s e n t e d here d e m o n s t r a t e d that aiprazolam induced analgesia in a genetic distinct way. In addtli(m, coadmhHslraliotl of the combinalion (}f opiolds and non opioid drugs ( HiOrl)hiue arid all)iaz()lamII ) ill I() I Im s pi Hal (()i-el, prod tic:col a nlarked syilerglsln ()f Ihe aHalgesic elfecl. The IiHdlHg Ihat the s y n e r g i s m had a n t a g o n i z e d Hah)x(me, iHdh'aled Iha{ al leas! some ()1 Ihe aHalgesic efle(:t of alprazolam is medialed by an opiokl me(hanism ()f acli()ll, hi ('oHchlsi(m, Ihe reported strain differences indlcale a ralher high degree ()f genelic segregation in alprazolam inducted analgesia. Such a finding suggesls lilac oploid a u d b e n z o d l a z e p i n e involvemenl in this analgesia can be infltmnced by genetic factors. I{EFEPd'~NClkS. 1. l'h'k, C.G., Chellg ,,l., l'aul,l)., and I'aslernak,G.W.,. Brain resevch 566, 295298 (1991). 2. Fernandez, F., Adams, F., and Ilolnms, V.F../. ('1i11. l~sychol~harnlacology7, 167-169 (1987). 3. l'asternak, G.W. The ,Iourllal ¢91 the Americall Meclical Association 259, 1 3 6 2 - 1 3 0 7 (1988).
ANTINOCICEPTIVE INTERACTION BETWEEN ALPRAZOLAM A N D OPIOIDS: GENETIC DIFFERENCES. Chaim G. Pick, Dept. of Anatomy and Anthropology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978 Israel. This s t u d y was designed to investigate the antinociceptive effects of one of the most prescribed benzodiazepines i.e. alprazolam. Groups of CD-1, BALB/c, C57BL a n d Swiss mice were treated with alprazolam, a d m i n i s t r a t e d alone or in c o m b i n a t i o n with morphine. Analgesia was assayed, using the r a d i a n t heat tailflick. Alprazolam (1 mg/kg, i.p.) elicited analgesia in BALB/c mice with an ED50 value of 1.1 m g / k g . No analgesia was observed in CD-1 or C57BL mice. The s e n s i t i v i t y of Swiss mice was weak. l n t r a t h e c a l a d m i n i s t r a t i o n o f alprazolam elicited analgesia in a d o s e - d e p e n d e n t m a n n e r in the BALB/c, Swiss a n d CD-1 mice. C57BL mice were completely inactive in the tailflick test after alprazolam injection. I n t r a c e r e b r o v e n t r i c u l a r a d m i n i s t r a t i o n elicit only very weak analgesia in the BALB/c mice. We f o u n d a synergistic increase in analgesia when a subthreshold dose of alprazolam was given with m o r p h i n e in the BALB/c mice. This interaction was antagonized by naloxone, indicating that at least some of the analgesic effects of alprazolam are m e d i a t e d by an opioid mechanism of action. No effect was found when alprazolam was coadministrated with o t h e r specific opioid agonists. Our results d e m o n s t r a t e that injections of alprazolam can produce analgesia u n d e r different genetic controls a n d modify morphine-induced antinociception in mice as assessed in the tailflick assay. Male CD-1, CFW(SW)BR (Swiss), C57BL/J6 (C57BL) a n d BALB/cAmNCrIBR (BALB/c) were uesed. Analgesia was determined, using the radiant heat tailflick technique as previously described( 1 ). Dose-response curves were analyzed, using a SPSS c o m p u t e r program and single-dose studies were analyzed, using the Fisher exact test. Following an i.p. injection, alprazolam elicited analgesia in a d o s e - d e p e n d e n t m a n n e r in BALB/c mice with ED50 value of 1.1 mg/kg. The Swiss mice were almost inactive a n d CD-1 a n d C57BL mice were completely inactive. Intrathecal administration of alprazolam elicited analgesia in a dosed e p e n d e n t m a n n e r in the BALB/c Swiss, and CD-1 mice. ED50 values were 10~g ,22.8~g and 34.6~tg, respectively. C57BL mice were completely inactive in the tailflick test after alprazolam injection. Intracerebroventricular administration did not elicit analgesia more than 13% (after 50 ~g in the BALB/c mice). In a separate tail-flick assay with BALB/c mice, alprazolam (2.5 mg/kg) p r o d u c e d analgesia in 70°,4 of the mice. Naloxone ( 1 mg/kg) abolished almost completely the analgesia response ( P< 0.05). Coadministration of alprazolam (0.1 mg/kg) with m o r p h i n e (1.0 m g / k g ) elicited analgesia in 70% of the BALB/c mice, naloxone (1 mg/kg) a n t a g o n i z e d this analgesia almost completely (P< 0.05). Next we assessed in the BALB/c mice the simultaneous a d m i n i s t r a t i o n of the selective agonists of ~, 8 and K1 receptor subtypes and alprazolam to evaluate the potential synergism between a l p r a z o l a m a n d opioid analgesia. When m o r p h i n e (Fig. 1) was coadministrated with alprazolam, we found a 5-fold shift to the left: The ED50 of m o r p h i n e without alprazolam was 3.2 m g / k g and with a l p r a z o l a m was 0.5 m g / k g . In c o n t r a s t to o u r findings with m o r p h i n e , no
224
synergism was fotmd or wllh [15(),4881 I.
when a fixed close of aiprazolam was given with DPDPE Morphine dose response curve with and without alprazolam.
I009080-
~"
70-
~
60-
"~
40-
/
Moq~hh~ ( rag&g,s.c.)
Mo~hine( mg/kg, s.c.) + Alpr~olmn (01• ,''
/
/
3020-
100.1
i
;0
Morphine Dose (mg/kg)
Alprazolam is known lo have a unique clinical spectrum among the high potent beHzodiazepim_'s. Clinical o b s e r v a t i o n s suggest that in some types of pain s y n d r o m e s , specifically Ihose inw}lvlng nerve injuries, alprazolam m a y be ttselul as an adjuHc! to narcotic analgesia for pain control (2). Like most n e u r o t r a u s m l t t e r s , tim opiates and opioid p e p t i d e s interact with multiple classes of receplors. Each sul)class has its UnklUe profile of ligand selectivity, regi(mal d i s l r i b u t l o n and pharmacological actions a n d each is c a p a b l e of moduhtlh~g the perceplJoH oJ pain. Classically, t~ receptors have been implicated in opiale analgesia, btml recent works indicate tim ability of a n u m b e r of opiold r e c e p l o r s y s t e m s Io elhi! analgesia l n d e p e n d e n l l y . I)I'I)PE have clearly d e m o n s t r a l e d ~3analgesic mechanisms. A highly KI-seleclive agonist U50,488 elhils seleclive KI analgesia arid naloxone b e n z o y l h y d r a z o n e (NalBzoll) has beeH a uselul tool in examJniHg ~3 analgesia (3). Tim d a t a p r e s e n t e d here d e m o n s t r a t e d that aiprazolam induced analgesia in a genetic distinct way. In addtli(m, coadmhHslraliotl of the combinalion (}f opiolds and non opioid drugs ( HiOrl)hiue arid all)iaz()lamII ) ill I() I Im s pi Hal (()i-el, prod tic:col a nlarked syilerglsln ()f Ihe aHalgesic elfecl. The IiHdlHg Ihat the s y n e r g i s m had a n t a g o n i z e d Hah)x(me, iHdh'aled Iha{ al leas! some ()1 Ihe aHalgesic efle(:t of alprazolam is medialed by an opiokl me(hanism ()f acli()ll, hi ('oHchlsi(m, Ihe reported strain differences indlcale a ralher high degree ()f genelic segregation in alprazolam inducted analgesia. Such a finding suggesls lilac oploid a u d b e n z o d l a z e p i n e involvemenl in this analgesia can be infltmnced by genetic factors. I{EFEPd'~NClkS. 1. l'h'k, C.G., Chellg ,,l., l'aul,l)., and I'aslernak,G.W.,. Brain resevch 566, 295298 (1991). 2. Fernandez, F., Adams, F., and Ilolnms, V.F../. ('1i11. l~sychol~harnlacology7, 167-169 (1987). 3. l'asternak, G.W. The ,Iourllal ¢91 the Americall Meclical Association 259, 1 3 6 2 - 1 3 0 7 (1988).