Cross-Tolerance to Acute Administration of MU and KAPPA Opioid Agonists at the Spinal Cord Level in the Rat

Abstract

Development of tolerance and cross-tolerance after acute administration of the μ agonist morphine and the K agonist U-50,488H was assessed in rats, through recording of a C-fiber-evoked spinal nociceptive reflex. Rats rendered tolerant to morphine (a single dose of 1 mg/kg i.p.) showed, after a 5-hour period, tolerance to morphine and cross-tolerance to the K-opioid receptor agonist U-50,488H, as revealed by depressed C-reflex responsiveness. In contrast, pretreatment with U-30,488H (a single dose of 1 mg/kg i.p.) rendered tolerant the rats to U-50,488H, but the animals did not develop cross-tolerance to morphine. Results indicate that acute administration of μ and K ligands leads to development of unidirectional cross-tolerance in rat spinal cord. This points to limitations in using alternated μ and K opiaid agonists to bypass the problem of development of opioid tolerance in chronic pain complaints.

Key Words:

• Spinal reflex
• morphine
• U-50
• 488H
• opioid receptors
• opiate tolerance
• analgesia
• rat