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 . 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.
Sakurada
Tsukasa
T
Department of Biochemistry, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan. tsukasa@daiichi-cps.ac.jp
Komatsu
Takaaki
T
Sakurada
Shinobu
S
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007278:Injections, Spinal; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism; D010146:Pain / Q000139:chemically induced* / Q000503:physiopathology*; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000378:metabolism
D000701:Analgesics, Opioid; D009569:Nitric Oxide; D013373:Substance P; D018698:Glutamic Acid; D009020:Morphine