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Vol. 286, Issue 2, 1000-1006, August 1998
Behavioral Pharmacology and Genetics Section, Intramural Research
Program, National Institute on Drug Abuse and Department of
Anesthesiology and Critical Care Medicine, Johns Hopkins University,
School of Medicine, Baltimore, Maryland
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 and
kappa 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 
-funaltrexamine,
[D-Ala2,Leu5,Cys6]enkephalin
or
(±)-(5,7a,8)-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.
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