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.