Actions of mu, kappa, sigma, delta and agonist/antagonist opiates on striatal dopaminergic function
Wood, P.L.; Stotland, M.; Richard, J.W.; Rackham, A.
Journal of Pharmacology and Experimental Therapeutics 215(3): 697-703
1980
ISSN/ISBN: 0022-3565 PMID: 6255136 Document Number: 157553
A sensitive gas chromatographic-mass fragmentographic assay was established for the simultaneous measurement of dihydroxyphenylacetic acid, homovanillic acid (HVA), dopamine (DA) and 3-methoxytyramine. By using this assay the actions of specific opiate receptor agonists on dopaminergic function were examined in the nigrostriatal pathway. In the rat, the mu agonists morphine, etorphine, methadone and phenazocine and the delta agonist D-Ala2-D-Leu5 enkephalin all produced dose-dependent elevations in the DA metabolites dihydroxyphenlacetic acid and HVA with no increase in 3-methoxytyramine. In the mouse, concomitant increases in HVA and 3-methoxytyramine were noted. The basis for this biochemical species difference in the coupling of intraneuronal metabolism and DA release remains to be determined. The epsilon agonist, .beta.-endorphin, also elevated striatal dihydroxyphenlacetic acid and HVA indicating the possible coexistence of these receptors with mu and delta receptors on nigrostiratal neurons. Experiments with the kappa agonists ketazocine, ethylketazocine and MR 2034 [(-)-.alpha.-(1R, 5R, 9R)-5, 9-dimethyl-2-(L-tetrahydrofurfuryl)-2'-hydroxy-6,7-benzomorphan] indicate the absence of kappa receptors on these neurons. Although the sigma agonist SKF 10047 (2'-hydroxy-5, 9-dimethyl-2-allyl-6, 7-benzomorphan) did after DA metabolism, this action did not appear to involve opiate receptors. The agonist/antagonist analgesics which possess multiple receptor affinities were found to elevate DA metabolites at low doses, with this action reversing at higher doses in which antagonistic activity prevails. The agonist action of these agents on DA metabolism does not appear to be mu or kappa receptor mediated and may therefore involve delta or epsilon receptors. A role for multiple opiate receptors was indicated in the regulation of nigrostriatal dopaminergic function but kappa receptors are not involved.