CALCIUM CHANNEL BLOCKADE BY CERTAIN OPIOIDS

DAVID EDWARD SEYLER, Purdue University

Abstract

Methadone (Dolophine('R)) and propoxyphene (Darvon('R)) exhibit some morphine-like characteristics but also differ from morphine, suggesting variations in mechanisms of action. Since methadone and propoxyphene structurally resemble the calcium channel blocker verapamil (Isoptin('R)), this thesis proposes that methadone and propoxyphene differ from morphine because they, like verapamil, block calcium channels. In parallel with verapamil, methadone and propoxyphene depressed barium-induced bovine adrenal catecholamine release and KCl-induced contractions of guinea pig ileum, which are known to be calcium dependent events. Calcium reversed opiate-induced depression in both tissues. Morphine did not affect either catecholamine release or ileal contractions. Similarly, procaine did not influence catecholamine release or ileal contraction, therefore, local anesthesia was eliminated as a mechanism of action for methadone and propoxyphene depression in these tissues. Opiates which block calcium channels should, like verapamil, produce bradycardia and hypotension. In the spinal vagotomized rat methadone, propoxyphene, and verapamil produced bradycardia and hypotension, whereas, morphine produced tachycardia and (at low doses) hypertension. If methadone and propoxyphene block calcium channels, and calcium channel blockage is involved in their toxicity, then verapamil pretreatment in mice should enhance this toxicity. As anticipated, verapamil reduced LD50s for methadone and propoxyphene in mice. Morphine's LD50 was also decreased by verapamil, possibly through increased blockage of central calcium channels. Pain relief by morphine is linked to reduced calcium binding and transport in the brain and calcium channel blockers may enhance morphine analgesia. However, methadone and propoxyphene may sufficiently block calcium channels so that verapamil does not enhance their induced analgesia. As expected, verapamil enhanced (p < 0.05) morphine, but not methadone or propoxyphene analgesia. Furthermore, intracerebroventricular calcium administration eliminated morphine analgesia but not that of methadone or propoxyphene. Modification of opiate analgesia by verapamil or by calcium probably depends on characteristics of the calcium channels affected by the opiate. The results of this thesis demonstrate that methadone and propoxyphene, in contrast to morphine, block calcium channels in a manner similar to verapamil, and that calcium channel blockade is important in the pharmacology and toxicology of these synthetic opiates.

Degree

Ph.D.

Subject Area

Pharmacology

COinS