PHARMACOLOGY OF THE ALLODYNIA IN RATS EVOKED BY HIGH-DOSE INTRATHECAL MORPHINE

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  • 1 February 1988
    • journal article
    • research article
    • Vol. 244  (2) , 501-507
Abstract
Morphine sulfate in doses of 90 to 150 .mu.g/3 .mu.l evoke a prominent behavioral syndrome characterized by 1) periodic bouts of spontaneous agitation during which the rat scratches and bites at the skin of the caudal dermatomes and 2) vigorous agitation, vocalization and coordinated efforts to bite and escape evoked by a light tactile stimulus applied to the flank, suggestive of a pain state (allodynia). The phenomenon is not reversed by naltrexone nor is it subject to tolerance. The ordering of activity of an opioid alkaloid related agent in producing this touch-evoked agitation is: noroxymorphone-3-glucuronide, morphine-3-glucuronide, morphine-3-ethereal sulfate, dihydromorphine, noroxymorphone dihydrate, hydromorphone, dihydrocodeine tartrate, morphine sulfate, dihydroisomorphine, morphine-HCl, 6-acetylmorphine, N-normorphine-HCl and (.sbd.)-morphine. The following agents were essentially without effect at the highest doses examined: 3,6-diacetylmorphine, N-normeperidine-HCl, nalorphine-HCl, alfentanil, sufentanil, naloxone, naltrexone, methadone, dextrorphan tartrate, meperidine-HCl, oxycodone, levorphanol, oxymorphone, codeine phosphate, thebaine, nalbuphine and naltrexone-3-glucuronide. The observations that the sulfated and conjugated metabolites are 10 to 50 times more potent than their unmetabolized precursor suggest the possibility that, in high concentrations certain phenantherene opioid alkaloids with a free 3-OH position, an ether bridge and no N-methyl extention will be subject to conjugation and this metabolite will alter the processing of otherwise innocuous tactile stimuli. The fact that the phenomenon appeared at least partially stereospecific may reflect upon the fact that other laboratories have shown that glucuronyl transferase may preferentially convert (.sbd.)-morphine to the 3-glucuronide and (+)-morphine to the 6-glucuronide which may be less active. We believe the present observation indicates that the coding of light tactile stimulation as non-noxious requires a tonic modulatory influence at the spinal cord level. The fact that morphine at high concentrations may exert anti-.gamma.-aminobutyric acid and antiglycinergic effects and the ability of certain spinally administered inhibitory amino acid antagonists to mimic this effect supports this hypothesis.