Opioid-induced cholecystokinin release in the CNS-neurochemical mechanisms and effects of sciatic nerve lesion
Sammanfattning: Cholecystokinin (CCK) and opioid peptides have a similar distribution in the nervous system and CCK has been demonstrated to counteract opioid-induced analgesia at spinal and supraspinal level. An increased spinal release of CCK has been suggested to be a mechanism for the relative resistance to opioid analgesic drug in certain pain conditions following nerve lesions (i.e. neuropathic pain). This thesis deals with the role of CCK after nerve injury and the interaction between opioids and CCK. The extracellular level of CCK-like immunoreactivity (CCK-LI) in the dorsal spinal cord of the anaesthetised rat was monitored by in vivo microdialysis. During the first week after complete sciatic nerve transection (axotomy), potassium stimulation (100 mM in the perfusion fluid) induced a significant release of spinal CCK-LI, which was higher than in control animals (albeit not significant). In contrast, two to eight weeks after axotomy potassium-stimulation failed to induce any release of CCK-LI. The ability of potassium to release CCK-LI after axotomy was restored by a CCK2 receptor antagonist. Morphine administered either systemically (2.5-5 mg/kg s.c.) or spinally (by perfusion of the dialysis probe with 100 [mu]M of morphine) induced a significant and naloxone-reversible release of CCK-LI in the dorsal horn of the spinal cord. The morphine- (5 mg/kg, s.c.) induced CCK-LI release was TTX-sensitive and calcium-dependent and could be prevented by topical application of either the L-type calcium channel blocker verapamil or the N-type calcium channel blocker [omega]-conotoxin GVIA. The morphine-induced release of CCK-LI in the dorsal horn was completely blocked by the d-opioid antagonist naltrindole, but not by the m-opioid receptor antagonist CTOP. A significant increase of the spinal CCK-LI level was also detected after systemic administration of the [delta]-opioid receptor agonist BW373U86 or spinal administration of the [delta]2-opioid receptor agonist [D-Ala2] deltorphin II. Systemic and spinal administration of the [mu]-opioid receptor agonist DAMGO (1 mg/kg, s.c. and 1[mu]M in the perfusion fluid) failed to alter the extracellular CCK-LI level. These findings indicate that the morphine-induced release of CCK-LI in the dorsal horn is mediated by the [delta]-opioid receptor. After peripheral axotomy, neither spinal nor systemic administration of morphine, at doses sufficient to induce a release of CCK-LI in normal rats, induced a release of CCK-LI. In contrast, the ability of d-opioid agonists to induce a release of CCK-LI was not affected by the nerve lesion. In summary, these data do not support the concept of an increased spinal CCK release as a mechanism for opioid resistance of deafferentiation pain. On the contrary, a marked reduction of the potassium- and morphine-induced release of CCK-LI was detected in the dorsal horn after nerve lesion. The apparent loss of potassium-induced CCK-LI release seems to involve CCK2 receptors, whereas the loss of the morphine-induced CCK-LI release may be due to a down regulation of d-opioid receptors. A possible mechanism for the potentiation of opioid analgesia by L- and N-type calcium channel blocking agents involving an inhibition of the release of CCK is suggested. In the limbic anterior cingulate cortex (ACC), which has a high density of CCK-immunoreactive neurons, an increased neuronal activity has been demonstrated in certain pain states. In the ACC, the potasssium-induced release of CCK-LI was found to be 4 - 6 times higher after axotomy, as compared to control animals, which may suggest a role of CCK for cortical processing of pain.
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