Mechanisms of Nociception Evoked by Intrathecal High-dose Morphine

Morphine is recommended by WHO as the analgesic of choice for effective treatment of moderate to severe cancer pain [World Health Organisation. Cancer pain relief, 2nd ed. Geneva: WHO; 1996]. Indeed spinally administered morphine at small doses injected intrathecally (i.t.) or intracerebroventricularly into animals produces a profound antinociception at both spinal and supraspinal sites. Conversely, high doses of spinally administered morphine elicit a series of scratching, biting and licking in mice, and vocalization and agitation in rats, indicative of a spontaneous nociceptive behavioural response. Hyperalgesia and allodynia are also induced by such morphine treatment in humans as well as animals. These behaviours are not an opioid receptor-mediated event. This article will review the potential mechanisms of spinally mediated nociceptive behaviour evoked by i.t. morphine at high concentrations. We will discuss a possible presynaptic release of nociceptive neurotransmitters/neuromodulators (e.g., substance P, glutamate and dynorphin) in the primary afferent fibers following i.t. high-dose morphine. There must be an intimate interaction of i.t. high-dose morphine with tachykinin neurokinin 1 (NK1) receptors and multiple sites on the N-methyl-d-aspartate (NMDA) receptor complex in the dorsal spinal cord. Since the effect of NMDA receptor activation and the associated Ca2+ influx results in production of nitric oxide (NO) by activation of NO synthase, it seems that spinal NO also plays an important role in nociception evoked by i.t. high-dose morphine. Morphine-3-glucuronide, one of the major metabolites of morphine, has been found to evoke nociceptive behaviour similar to that of i.t. high-dose morphine. It is plausible that morphine-3-glucuronide may be responsible for nociception seen after i.t. high-dose morphine treatment. The demonstration of neural mechanism underlying morphine-induced nociception provides a pharmacological basis for improved pain management with morphine at high doses.