Analgesic cross-tolerance between morphine and opioid peptides

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Abstract
The analgesic effect, of intracerebroventricular administration of morphine, ketocyclazocine, [D-ala2]-methionine enkephalinamide (DAM), [D-ala2-D-leu5]-enkephalin. (DADLE), leuenkephalin, metenkephalin, and β-endorphin on acetic acid-induced abdominal writhing (AAW) was investigated in naive and morphine-tolerant mice. It was found that the relative potencies of a series of opioids are different in naive and morphine-tolerant groups. In naive animals, the order of potency (ED50, nmol) was β-endorphin > morphine=DAM > DADLE > ketocyclazocine=leuenkephalin=metenkephalin. The morphine-tolerant animals were cross-tolerant to ketocyclazocine and to all the peptides studied; DAM and β-endorphin exhibited the highest degree of tolerance. In morphine-tolerant animals, the order of potency was morphine=DADLE=β-endorphin > DAM=ketocyclazocine =metenkephalin > leuenkephalin. The results indicate that endogenous opioid systems may be affected by tolerance development to morphine.