Regulation of morphine antiallodynic efficacy by cholecystokinin in a model of neuropathic pain in rats.
Neuropathic pains have often been classified as opioid-resistant. Here, spinal (intrathecal) actions of morphine and nonmorphine opioids have been studied in a nerve ligation model of neuropathic pain in rats. Mechanical allodynia was evaluated using von Frey filaments. Nerve-injured animals exhibited allodynia that was stable for up to 6 weeks after the surgery. Morphine did not alter allodynia at doses up to 300 nmol (100 micrograms). In contrast, [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO), a high-efficacy mu opioid agonist, produced a significant, dose-related antiallodynic action. [D-Ala2, Glu4]deltorphin (delta agonist) produced a significant antiallodynic effect only at 300 nmol, reaching approximately 70% of the maximum. Coadministration of morphine with a dose of [D-Ala2, Glu4]deltorphin, which was inactive alone, produced a significant and long-lasting antiallodynic action that was antagonized by NTI (delta receptor antagonist); NTI alone had no effect. Although blockade of cholecystokinin-B (CCKB) receptors with L365,260 did not produce effects alone, a significant antiallodynic action was observed when coadministered with morphine; this elevation of nociceptive threshold was abolished by NTI. The finding that DAMGO, but not very large doses of morphine, produced antiallodynic actions suggests that the ability of mu opioids to alleviate the allodynia is related, in part, to efficacy at postsynaptic mu receptors. At an inactive dose, a delta agonist or a CCKB antagonist enhanced morphine antiallodynic efficacy in an NTI-sensitive fashion. CCKB receptor blockade may enhance endogenous enkephalin actions, resulting in enhancement of morphine efficacy through a mu-delta receptor interaction.
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, USA.
M L
ML
Nichols
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Bian
M H
MH
Ossipov
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J
Lai
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Porreca
D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001570:Benzodiazepinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002766:Cholecystokinin / Q000037:antagonists & inhibitors / Q000502:physiology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000503:physiopathology; D010671:Phenylurea Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley
D000701:Analgesics, Opioid; D001570:Benzodiazepinones; D010671:Phenylurea Compounds; C058121:L 365260; D009020:Morphine; D002766:Cholecystokinin