PT  - JOURNAL ARTICLE
AU  - Li Zhou
AU  - Qin Zhang
AU  - Christoph Stein
AU  - Michael Schäfer
TI  - Contribution of Opioid Receptors on Primary Afferent Versus Sympathetic Neurons to Peripheral Opioid Analgesia
DP  - 1998 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1000--1006
VI  - 286
IP  - 2
4099  - http://jpet.aspetjournals.org/content/286/2/1000.short
4100  - http://jpet.aspetjournals.org/content/286/2/1000.full
SO  - J Pharmacol Exp Ther1998 Aug 01; 286
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics