GABA agonists enhance morphine and fentanyl antinociception in rabbit tooth pulp and mouse hot plate assays

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Abstract
Parallel experiments in the rabbit tooth pulp and mouse hot plate paradigms were performed to elucidate the effect of pretreatment with the GABA mimetic compound muscimol (M) and diazepam (DZ) on the antinociceptive effect of both morphine sulfate (MS) and fentanyl citrate (F). The ED50 values for F in both rabbits and mice were lowered significantly (p ≤ 0.05) by pretreatment with either i.v. DZ or M in rabbits or i.p DZ or i.v. M in mice. There was a significant 7‐fold shift of the F dose‐response curve after pretreatment with M in rabbits and a 3‐fold shift in mice compared to controls; a 10‐fold shift after pretreatment with i.v. DZ in rabbits and a 2‐fold shift after i.p DZ in mice. The ED50 values for MS in both rabbits and mice were lowered significantly (p ≤ 0.05) by pretreatment with i.v. muscimol but not DZ (p ≤ 0.18). Similarly, pretreatment with i.v. M, in rabbits and mice, but not i.v DZ in rabbits or i.p DZ in mice, significantly shifted the dose‐response curves of MS to the left compared to controls. DZ and M i.v. significantly prolonged the duration of antinociception (rabbit) of an ED98 dose of MS and ED90 dose of F. Time to 50% maximal possible antinociceptive effect (MPE) increased from 240 min for MS + vehicle to 425 min for MS + DZ, and over 450 min for MS + M. Time to 50% MPE increased from 25 min for F + vehicle to 38 min for F + DZ. Similar results were observed for F + M. DZ pretereatment enhances the antinociceptive potency of 2X ED50 of F. In general, the average % MPE of F + DZ was twice tha tof F + vehicle over the first 20 min postopioid injection. A similar trend was noted following 2 × ED50 pf MS, whereas scopolamine had no significant effect. These results suggest that GABAA agonists, both direct M and indirect DZ enhance the antinociceptive effect of the opioids F and MS. since naloxone completely reversed this effect and scopolamine had no significant effect, this implies that GABAA agonists enhance opioid antinociception by an opioid and not a cholinergic mechanism.