Monoamine and opioid interactions in spinal analgesia and tolerance

Noradrenergic and serotonergic neurons, originating in the brainstem and terminating in the dorsal horn, modulate the spinal processing of nociception. The inhibitory effects of norepinephrine (NE) and serotonin (5-HT) on elements of nociceptive transmission may be direct, or secondary to the release of neuromodulators such as opioid peptides. Two major criteria have been used in pharmacological studies of spinal opioid and monoamine interactions: the ability of opioid antagonists to attenuate the antinociceptive effects evoked by stimulating the release of endogenous NE and 5-HT in the lumbar spinal cord, or by the intrathecal injection of exogenous NE and 5-HT; and the development of cross tolerance between opioids and each of NE and 5-HT. Evidence regarding the spinal interaction between opioids and monoamines in mediating behavioural analgesia is reviewed. Recent results from this laboratory indicate that IT (-)naloxone but not (+)naloxone produces dose-dependent antagonism of IT NE-induced antinociception in the rat. This effect was not due to hyperalgesia. In rats made tolerant to spinal morphine using continuous IT infusion, the antinociceptive effect of continuous IT NE was significantly attenuated. However, no cross tolerance was observed between morphine and 5-HT. Observations from a variety of studies support the hypothesis of a spinal opioid link which contributes, in part, to NE-induced antinociception. However, this interaction remains to be conclusively established.