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Volume 17, Number 10, Issue of May 15, 1997 pp. 3907-3912
Copyright ©1997 Society for Neuroscience

Dissociation of Tolerance and Dependence for Opioid Peripheral Antinociception in Rats

Received Jan. 13, 1997; revised Feb. 20, 1997; accepted Feb. 27, 1997.

K. O. Aley and J. D. Levine

Departments of Anatomy, Medicine, and Oral Surgery, and Division of Neuroscience, University of California, San Francisco, California 94143

Repeated peripheral administration of the µ-opioid agonist [D-Ala²,N-Me-Phe⁴,gly⁵-ol] enkephalin (DAMGO) produces acute tolerance and dependence on its peripheral antinociceptive effect against prostaglandin E₂ (PGE₂)-induced mechanical hyperalgesia. In this study we evaluated the roles of protein kinase C (PKC) and nitric oxide (NO) in the development of this tolerance and dependence. Repeated administration of PKC inhibitors chelerythrine and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride with DAMGO did not alter the tolerance to DAMGO; however, dependence (defined as naloxone-induced withdrawal hyperalgesia) was blocked. Repeated administration of N-(n-heptyl)-5-chloro-1-naphthalenesulfonamide, a PKC activator, which alone did not produce tolerance, mimicked the dependence produced by DAMGO. Repeated administration of the NO synthase inhibitor N^G-methyl-L-arginine with DAMGO blocked the development of tolerance to DAMGO but had no effect on the development of dependence. Repeated administration of L-arginine, a NO precursor, mimicked tolerance produced by repeated administration of DAMGO (i.e., the antinociceptive effect of DAMGO was lost); however, L-arginine did not mimic dependence. These findings suggest that the development of acute tolerance and dependence on the peripheral antinociceptive effects of DAMGO have different, dissociable mechanisms. Specifically, PKC is involved in development of µ-opioid dependence, whereas the NO signaling system is involved in the development of µ-opioid tolerance.

Key words: µ-opioids; nitric oxide; pain; protein kinase C; second messenger systems; withdrawal

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