Midazolam-induced hyperalgesia in rats: modulation via GABA(A) receptors at supraspinal level

The effect of benzodiazepines on the nociceptive threshold was studied in r ats using the tail-flick and the formalin tests. Systemic injection of mida zolam (10 mg/kg, i.p.) induced a significant decrease of the tail-flick lat ency and produced a long-lasting nociceptive effect in the formalin test, t hus characterising a hyperalgesic state. The hyperalgesia induced by midazo lam in the tail-flick test was blocked by flumazenil, a specific antagonist for benzodiazepine sites associated with GABA, receptors. Picrotoxin, a Cl - channel blocker, inhibited midazolam-induced hyperalgesia in both tests. Midazolam caused hyperalgesia when administered intracerebroventricularly ( i.c.v.; 25 mu g) but not intrathecally (i.t.; 75 mu g). I.c.v. but not i.t. (5 mu g) injection of flumazenil suppressed the hyperalgesia induced by mi dazolam (10 mg/kg, i.p.). Combination of non-hyperalgesic doses of diazepam (10 mg/kg, i.p.) or ethanol (0.48 g/kg, oral) with midazolam (5 mg/kg, i.p .) also induced hyperalgesia. Our results demonstrate that midazolam and di azepam alone or in combination with ethanol can produce hyperalgesia by int eracting with GABA, receptors at the supraspinal level in rats. The risk of hyperalgesia should be taken in account when these drugs are used in combi nation in humans. (C) 1999 Elsevier Science B.V. All rights reserved.