A local serotonergic component involved in the spinal antinociceptive action of morphine

Participation of opiate, serotonergic and noradrenergic components in the antinociceptive action of intrathecally administered morphine was evaluated by measuring the ability of subcutaneously administered doses of naloxone, methysergide and phentolamine to alter analgesia. Morphine produced a dose-dependent elevation of the tail-flick latency, due exclusively to local spinal actions. For example, 10 nmol of the drug, when administered intrathecally in rats with bilateral lesions of the dorsolateral funiculus, produced an increase in the tail-flick latency, that was similar to that observed in intact animals. Furthermore, morphine was ineffective when administered intracerebroventricularly into the fourth ventricle of intact rats. The spinal antinociceptive action of the opiate was antagonized by naloxone (ID50 = 0.035 mg/kg, s.c.) but was also significantly attenuated by methysergide (ID50 = 4.28 mg/kg, s.c.). Phentolamine was ineffective. Doses of methysergide that were most effective in reversing the spinal action of morphine also produced hyperalgesia when administered alone. On the other hand, when the dorsolateral funiculus was lesioned, the hyperalgesia was no longer observed, yet the antagonist remained effective against morphine. These data suggested that the doses of methysergide needed to antagonize the action of morphine were in the same range as those needed to block the synaptic actions of serotonin (5-HT) released from the tonically-acting, descending pain inhibitory nerves. The results demonstrate that local opiate, as well as serotonergic, mechanisms mediate the antinociceptive action of morphine in the spinal cord. The recruitment of a serotonergic component may be related to an action of opiates within the spinal cord, to cause the release of serotonin from the terminal fields of the spinipetal serotonergic nerves.