Dissociation of Tolerance and Dependence for Opioid Peripheral Antinociception in Rats

K. O. Aley, J. D. Levine
1997 Journal of Neuroscience  
Repeated peripheral administration of the -opioid agonist [D-Ala 2 ,N-Me-Phe 4 ,gly 5 -ol] enkephalin (DAMGO) produces acute tolerance and dependence on its peripheral antinociceptive effect against prostaglandin E 2 (PGE 2 )-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
more » ... yl)-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 syn-thase 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 -opioid dependence, whereas the NO signaling system is involved in the development of -opioid tolerance.
doi:10.1523/jneurosci.17-10-03907.1997 pmid:9133408 fatcat:vof43t42wbg7xnip5n256aieia