Naloxone-sensitive and GABAA receptor mediated analgesic response of benzodiazepines in mice

Various benzodiazepines (BZs) were investigated for their analgesic effect by the tail-flick method in mice. Central type BZ-receptor agonists such as clonazepam, chlordiazepoxide and diazepam showed analgesia while the peripheral BZ-receptor binding agent, Ro 5-4864, and the BZ micromolar binding agent phenytoin, failed to show any effect. Other BZs, such as lorazepam and nitrazepam, were ineffective in producing analgesia. Pretreatment with naloxone antagonized the analgesic effect of central type BZ-receptor agonists. Similarly, pretreatment with Ro 15-1788, a central BZ-receptor antagonist, also blocked the analgesic effect. When the involvement of the GABAergic system in the analgesic response of BZ agonists was investigated, a potentiation of BZ action was seen as a combination of a subeffective dose of clonazepam with a subanalgesic dose of muscimol, a specific GABAA agonist, showed an enhanced effect. Moreover, pretreatment with GABAergic substances like pentobarbitone also showed a facilitatory effect on BZ-induced analgesia. On the other hand, a combination of clonazepam with baclofen, a specific GABAB agonist, failed to show any synergistic effect. The analgesic effect of central type BZ-receptor agonists was found to be bicuculline reversible. It is concluded that GABAA receptor activation has a modulatory role in the naloxone sensitive analgesic effect of central type BZ-receptor agonists.