Antianalgesic action of dynorphin A mediated by spinal cholecystokinin.
Previous work indicates that the antianalgesic action of pentobarbital and neurotensin administered intracerebroventricularly in mice arises from activation of a descending system to release cholecystokinin (CCK) in the spinal cord where CCK is known to antagonize morphine analgesia. Spinal dynorphin, like CCK, has an antianalgesic action against intrathecally administered morphine. This dynorphin action is indirect; even though it is initiated in the spinal cord, it requires the involvement of an ascending pathway to the brain and a descending pathway to the spinal cord where an antianalgesic mediator works. The aim of the present investigation was to determine if the antianalgesic action of intrathecal dynorphin A involved spinal CCK. All drugs were administered intrathecally to mice in the tail flick test. Morphine analgesia was inhibited by dynorphin as shown by a rightward shift of the morphine dose-response curve. The effect of dynorphin was eliminated by administration of the CCK receptor antagonists lorglumide and PD135 158. One hour pretreatment with CCK antiserum also eliminated the action of dynorphin. On the other hand, the antianalgesic action of CCK was not affected by dynorphin antiserum. Thus, CCK did not release dynorphin. Both CCK and dynorphin were antianalgesic against DSLET but not DPDPE, delta 2 and delta 1 opioid receptor peptide agonists, respectively. The results suggest that the antianalgesic action of dynorphin occurred through an indirect mechanism ultimately dependent on the action of spinal CCK.
Rady
J J
JJ
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, USA. jrady@mcw.edu
Holmes
B B
BB
Fujimoto
J M
JM
D000698:Analgesia; D000700:Analgesics / Q000037:antagonists & inhibitors*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D002766:Cholecystokinin / Q000037:antagonists & inhibitors / Q000502:physiology*; D004399:Dynorphins / Q000494:pharmacology* / Q000502:physiology*; D020881:Enkephalin, D-Penicillamine (2,5)-; D004743:Enkephalin, Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004745:Enkephalins / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D007278:Injections, Spinal; D008297:Male; D008536:Meglumine / Q000008:administration & dosage / Q000031:analogs & derivatives; D051379:Mice; D009020:Morphine / Q000008:administration & dosage; D011377:Proglumide / Q000008:administration & dosage / Q000031:analogs & derivatives; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors; D017465:Receptors, Opioid, delta / Q000819:agonists; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology*
D000700:Analgesics; D000906:Antibodies; D004745:Enkephalins; D007211:Indoles; D011949:Receptors, Cholecystokinin; D017465:Receptors, Opioid, delta; C065600:PD 135158; D004743:Enkephalin, Leucine; D008536:Meglumine; D004399:Dynorphins; C034318:enkephalin, Ser(2), Leu(5), Thr(6)-; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; D002766:Cholecystokinin; D011377:Proglumide; C048181:lorglumide