Spinal opioid analgesic effects are enhanced in a model of unilateral inflammation/hyperalgesia: possible involvement of noradrenergic mechanisms.
We have examined the spinal analgesic activity of opioid agonists and antagonists in a model of short term, unilateral, carrageenan-induced inflammation/hyperalgesia. Rats received a single s.c. injection of carrageenan (2-6 mg in saline) 3-24 h prior to testing hindpaw withdrawal latencies to noxious thermal stimuli. Dose-response curves for intrathecally administered agonists with mu- and/or delta-opioid activity were shifted to the left for inflamed hindpaws when compared to contralateral non-inflamed paws. The selective kappa-receptor agonist U-50,488H had no activity in this analgesic assay on either inflamed or non-inflamed paws when administered intrathecally. However, systemic administration of U-50,488H did produce significant elevations of paw withdrawal latencies in inflamed paws. The alpha 2-adrenoceptor agonist clonidine also produced dose-dependent antinociception in the paw withdrawal assay after systemic or intrathecal administration. Inflamed hindpaws were significantly more sensitive to the antinociceptive effect of morphine on inflamed hindpaws was blocked by the opioid antagonist naloxone or the alpha 2-adrenoceptor antagonist idazoxan. The effect of clonidine was only blocked by idazoxan. Antagonists alone had no significant effect on withdrawal latencies. The data indicate that the analgesic action of opioids during conditions of inflammation may depend on an interaction with spinal noradrenergic pathways.
Hylden
J L
JL
Neurobiology and Anesthesiology Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892.
Thomas
D A
DA
Iadarola
M J
MJ
Nahin
R L
RL
Dubner
R
R
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002351:Carrageenan; D003000:Clonidine / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009292:Narcotic Antagonists; D009619:Nociceptors / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects*
D000317:Adrenergic alpha-Antagonists; D004745:Enkephalins; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D009020:Morphine; D002351:Carrageenan; D003000:Clonidine