Differential modulation of alpha 2-adrenergic and opioid spinal antinociception by cholecystokinin and cholecystokinin antagonists in the rat dorsal horn: an electrophysiological study.
Cholecystokinin (CCK) has been shown to reduce the spinal antinociceptive effects of opioid agonists such as morphine. The present study examined the effect of CCK and CCKB antagonists on the spinal antinociception mediated by the selective alpha 2-adrenergic agonist dexmedetomidine. Extracellular recordings of noxious-evoked C fibre responses of dorsal horn convergent neurones were made in the halothane-anaesthetized rat. Alone, intrathecal dexmedetomidine (5 micrograms) profoundly inhibited C fibre-evoked responses (92 +/- 7%). In the presence of 1 microgram intrathecal CCK the antinociceptive effect of dexmedetomidine was reduced to 27 +/- 11%. Inhibitions of C fibre-evoked responses mediated by submaximal doses (0.5 and 2.5 micrograms) dexmedetomidine were not altered by CCKB antagonists L365,260 (0.2 mg/kg subcutaneous) or PD135158 (10 micrograms intrathecal). Both CCKB antagonists did increase the inhibition of C fibre-evoked responses by the mu opioid agonists DAGOL and morphine. The results suggest CCK is able to inhibit spinal antinociception mediated via the activation of alpha 2-adrenergic receptors in addition to its well-documented interaction with spinal opioid analgesia. However the antagonist studies indicate an endogenous CCK control of spinal mu opioid mediated antinociception which does not extend to alpha 2-adrenergic antinociception.
Department of Pharmacology, University College London, UK.
A F
AF
Sullivan
K
K
Hewett
A H
AH
Dickenson
D000700:Analgesics / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D002766:Cholecystokinin / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004594:Electrophysiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D020926:Medetomidine; D008536:Meglumine / Q000031:analogs & derivatives / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology; D009412:Nerve Fibers / Q000187:drug effects; D010671:Phenylurea Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors; D011957:Receptors, Opioid / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects*
D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D004745:Enkephalins; D007093:Imidazoles; D007211:Indoles; D010671:Phenylurea Compounds; D018341:Receptors, Adrenergic, alpha-2; D011949:Receptors, Cholecystokinin; D011957:Receptors, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C065600:PD 135158; C058121:L 365260; D008536:Meglumine; D009020:Morphine; D002766:Cholecystokinin; D020926:Medetomidine