The role of vasopressin on the effect of U-50,488 to block the development of morphine tolerance and physical dependence

Abstract

U-50,488, a selective kappa-opioid receptor agonist, has been reported to inhibit the development of antinociceptive tolerance to morphine in mice, rats and guinea pigs, but the mechanism involved in this action remains unknown. Since U-50,488 has been reported to suppress the plasma vasopressin level, we investigated the role of vasopressin with U-50,488 in the male Sprague Dawley rat in this study. Animals (230-270 g) were chronically treated with morphine (10 mg/kg, i.p.) twice a day for 6 days in order to induce tolerance to antinociceptive effect measured by tail-flick test. Withdrawal symptoms were precipitated by naloxone (10 mg/kg, i.p.) on day 7. U-50,488 (i.p.) or AVP (i.p. or i.c.v.) or U-50,488 and AVP was (were) coadministered with chronic morphine to investigate their effects on morphine tolerance and dependence. We found that coadministration of 8 mg/kg U-50,488 (i.p.) with morphine almost completely block morphine tolerance and partially block withdrawal symptoms. In contrast, coadministration of AVP (0.3 microgram/kg, i.p., or 0.01 microgram, i.c.v.) with morphine and U-50,488, the effects of U-50,488 to block morphine tolerance and dependence were reversed. In addition, treatment of AVP antagonist (dPTyr(Me)AVP, 0.5 microgram/kg, i.p. or 0.5 microgram, i.c.v.) has the similar effect as U-50,488 to block morphine tolerance. In summary, the effect of U-50,488 to block morphine tolerance and dependence may relate to its inhibitory effect on AVP release.

Blockade of the development of morphine tolerance by U‐50,488, an AVP antagonist or MK‐801 in the rat hippocampal slice

“…U‐50,488 ( trans ‐3,4‐dichloro‐N‐methyl‐N‐[2‐(1‐pyrrolidinyl)‐cyclohexyl]‐benzeneacetamide hydrochloride), a selective K ‐opioid receptor agonist, has been shown to suppress the development of antinociceptive tolerance to morphine in rats (Yamamoto et al , 1988), mice (Takahashi et al , 1991) and guinea‐pigs (Tao et al , 1994). The mechanism may involve the activation of K ‐opioid receptors and an inhibitory effect of U‐50,488 on vasopressin release (Tao et al , 1997). Xu et al (1992) demonstrated that concomitant intracerebroventricular (i.c.v.)…”

“…with morphine (i.p.) blocked the development of morphine tolerance in rats (Tao et al , 1997). Recently, both competitive and non‐competitive N‐methyl‐D‐aspartate (NMDA) antagonists (Trujillo & Akil, 1991; Marek et al , 1991; Tiseo & Inturrisi, 1993), and nitric oxide synthase inhibitors (Kolesnikov et al , 1992; Majeed et al , 1994) have been found to prevent the development of morphine tolerance, suggesting that the development of morphine tolerance may also involve the activation of NMDA receptors and NO production.…”