The Journal of Neuroscience, April 1, 2001, 21(7):2536-2545
Contribution of Endogenous Enkephalins to the Enhanced Analgesic
Effects of Supraspinal µ Opioid Receptor Agonists after Inflammatory
Injury
Robert W.
Hurley and
Donna L.
Hammond
Department of Anesthesia and Critical Care and The Committee on
Neurobiology, University of Chicago, Chicago, Illinois 60637
This study examined a mechanism responsible for the enhanced
antihyperalgesic and antinociceptive effects of the µ opioid receptor
agonist (ORA) [D-Ala2,
NMePhe4, Gly5-ol]enkephalin
(DAMGO) microinjected in the rostroventromedial medulla (RVM) of rats
with inflammatory injury induced by injection of complete Freund's
adjuvant (CFA) in one hindpaw. In rats injected with CFA 4 hr earlier,
microinjection of the µ opioid receptor antagonist
D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2
(CTAP) in the RVM antagonized both the marginal enhancement of the
potency of DAMGO and its antinociceptive effect. The
opioid
receptor antagonist naltriben (NTB) was without effect. In rats
injected with CFA 2 weeks earlier, CTAP antagonized the effects of
DAMGO to a lesser extent. However, NTB completely prevented the
enhancement of the potency of DAMGO, whereas it did not antagonize
DAMGO's antinociceptive effects. Microinjection of NTB alone, but not
CTAP in the RVM of CFA-treated rats, enhanced the hyperalgesia present
in the ipsilateral hindpaw and induced hyperalgesia in the
contralateral, uninjured hindpaw. These results suggest that persistent
inflammatory injury increased the release in the RVM of opioid peptides
with preferential affinity for the
opioid receptor, which can
interact in a synergistic or additive manner with an exogenously
administered µ opioid receptor agonist. Indeed, the levels of
[Met5]enkephalin and
[Leu5]enkephalin were increased in the RVM and in
other brainstem nuclei in CFA-treated rats. This increase most likely
presents a compensatory neuronal response of the CNS of the injured
animal to mitigate the full expression of inflammatory pain and to
enhance the antinociceptive and antihyperalgesic effects of exogenously
administered µ opioid receptor analgesics.
Key words:
µ opioid receptor;
opioid receptor; antinociception; complete Freund's adjuvant; hyperalgesia; nucleus
raphe magnus
Copyright © 2001 Society for Neuroscience 0270-6474/01/2172536-10$05.00/0