Morphine-induced in vivo release of spinal cholecystokinin is mediated by delta-opioid receptors - effect of peripheral axotomy

Morphine and other opioid agonists induce spinal in vivo release of cholecy stokinin (CCK), a neuropeptide with antiopioid properties. However, so far the opioid receptor subtype responsible for this effect has not been determ ined. In the present in vivo microdialysis study, the morphine-induced rele ase of cholecystokinin-like immunoreactivity (CCK-LI) in the dorsal horn wa s completely blocked by the delta -opioid antagonist naltrindole (10 muM in the perfusion fluid). Neither the mu -opioid receptor antagonist D-Phe-Cys -Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP; 10 muM in the perfusion fluid), nor the kappa -opioid receptor antagonist nor-binaltorphimine (nor-BNI); 10 mu M in the perfusion fluid) had any significant effect in this respect. In ad dition, systemic administration of the delta -opioid receptor agonist BW373 U86 (1 mg/kg, s.c.) and spinal administration of the delta (2)-opioid recep tor agonist, Tyr-D-Ala-Phe-Glu-Val-Val-Gly amide ([D-Ala(2)] deltorphin II) (1 muM in the perfusion fluid) induced a significant increase of the CCK-L I level. The effect of BW373U86 on spinal CCK-LI release was completely blo cked by spinal administration of naltrindole. The mu -opioid receptor agoni st [D-ala(2)-N-Me-Phe(4)-Gly(5)-ol]-enkephalin (DAMGO) (1 muM in the perfus ion fluid or 1 mg/kg, s.c.) failed to alter the CCK-LI level. Peripheral ne rve lesions have previously been shown to down-regulate mu- and delta -opio id receptors in the dorsal horn, to increase the gene-expression of CCK and CCK-receptor mRNA in dorsal root ganglion neurons and to alter the potassi um-induced spinal CCK-LI release. After complete sciatic nerve transection, administration of the two selective delta -opioid receptor agonists induce d a significant release of CCK-LI, which was comparable to controls. In con trast, neither systemic nor spinal administration of morphine and DAMGO alt ered the spinal CCK-LI release in axotomized animals. The present data indi cate that the delta -opioid receptor mediates morphine-induced CCK-LI relea se in the spinal cord.