Abstract
Opioid receptors are synthesized in dorsal root ganglia and transported into peripheral terminals of primary afferent neurons. Activation of such receptors results in antinociceptive effects that are most prominent in inflammation. In addition, opioid receptors located on sympathetic postganglionic neuron terminals may be involved in these effects. This study investigates the peripheral analgesic efficacy of the mu, delta and kappa receptor agonists [d-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin, [d-Pen2,5]-enkephalin and trans-(±)3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide, the effective number of peripheral mu, delta andkappa receptors in relation to the development of inflammation and the contribution of sympathetic vs. sensory neurons by use of capsaicin and 6-hydroxydopamine, respectively. In Wistar rats with Freund’s adjuvant-induced hindpaw inflammation, antinociceptive effects of intraplantar [d-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (1.0–32 μg), [d-Pen2,5]-enkephalin (10–100 μg) and trans-(±)3,4-Dichloro-N-methyl-N-[2-(l-pyrrolidiny)-cyclohexyl]-benzeneacetamide (10–100 μg) were evaluated by paw pressure test. These effects increased linearly between 6 and 24 hr, but did not change between 24 and 96 hr of inflammation, whereas the doses of the irreversible antagonists β-funaltrexamine, [d-Ala2,Leu5,Cys6]enkephalin or (±)-(5β,7a,8β)-3,4-dichloro-N-[3-methylene-2-oxo-8-(1-pyrrolidinyl)-1-oxaspir[4,5]dec-7-yl]benzeneacetamide required to abolish the respective agonist effects increased between 12 and 96 hr. Pretreatment with capsaicin (30, 50, 70 mg/kg s.c. over 3 days) but not with 6-hydroxydopamine (75 mg/kg i.p. over 3 days) reversed the hyperalgesia in inflamed paws and almost abolished antinociceptive effects of all three agonists. These results suggest that the increased opioid agonist efficacy is due to an increased number of peripheral opioid receptors at later stages of inflammation and that peripheral opioid antinociceptive effects are primarily mediated by mu, delta and kappa opioid receptors on primary afferent neurons.
Footnotes
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Send reprint requests to: Dr. Michael Schäfer, Department of Anesthesiology and Critical Care Medicine, Freie Universitaet Berlin, University Hospital Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany.
- Abbreviations:
- BK
- bradykinin
- CGRP
- calcitonin gene-related peptide
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin
- DALCE
- [d-Ala2,Leu5,Cys6]enkephalin
- DPDPE
- [d-Pen2,5]-enkephalin
- DRG
- dorsal root ganglia
- CFA
- complete Freund’s adjuvant
- β-FNA
- β-funaltrexamine
- i.pl.
- intraplantar
- 6-OHDA
- 6-hydroxydopamine
- PAN
- primary afferent neurons
- PPT
- paw pressure threshold
- SMBU-1
- (±)-(5β,7a,8β)-3,4-dichloro-N-[3-methylene-2-oxo-8-(1-pyrrolidinyl)-1-oxaspir[4,5]dec-7-yl]benzeneacetamide
- SPN
- sympathetic postganglionic neurons
- U50
- 488H, trans-(±)3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidiny)-cyclohexyl]-benzeneacetamide
- ANOVA
- analysis of variance
- Received July 22, 1997.
- Accepted March 4, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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