Role of spinal 5-HT(1A) receptors in morphine analgesia and tolerance in rats.

We here studied the involvement of spinally located 5-HT(1A) and opioid receptors, in the paradoxical effects that their activation can produce on nociception. Intrathecal (i.t.) injection of the 5-HT(1A) receptor agonist 8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT) (1-10 microg) induced analgesic effects in the formalin model of tonic pain whereas in the paw pressure test, it decreased the vocalization threshold. In this latter test, i.t. 8-OH-DPAT also markedly reduced the analgesic effect of systemic morphine (5-10 mg/kg, s.c.). At 10 microg, 8-OH-DPAT totally abolished the effect of 5 mg/kg of morphine; this inhibitory effect was antagonized by pre-treatment with 0.63 mg/kg of the 5-HT(1A) antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)-cyclohexanecarboxamide-trihydrochloride). In contrast, the i.t. injection of WAY-100635 (1-10 microg) dose-dependently potentiated the antinociceptive activity of a dose of morphine (2.5 mg/kg, s.c.). Furthermore, WAY-100635 (10 microg, i.t.) potentiated morphine analgesia in morphine-tolerant rats. These findings demonstrate that 5-HT(1A) receptor agonists can act in the spinal cord to produce both hyper- and hypo-algesic effects and play a major role in the opioid analgesia and tolerance.