Potential involvement of tyrosine phosphatase and calpain-related pathways in opioid withdrawal syndrome in mice

Abstract

The present study was designed to determine the effect of N'-[6,7-dichloro-4-(4-methoxy-phenyl)-3-oxo-3,4-dihydroquinoxalin-2-yl] hydrazide (SJA 7019), a selective nonpeptide inhibitor of calpain, and sodium orthovanadate, a selective inhibitor of tyrosine phosphatase, on the development of physiological dependence, as assessed by precipitated morphine withdrawal behavior in mice. Subchronic morphine administration (5 mg/kg, intraperitoneally, twice daily for 5 days), followed by a single injection of naloxone was used to precipitate the opioid withdrawal syndrome in mice. Behavioral observations were made immediately after naloxone treatment. Withdrawal syndrome was assessed quantitatively in terms of the withdrawal severity score and the frequency of jumping, rearing, forepaw licking, and circling. Daily single administration of SJA 7019 (1.5, 3, and 6 mg/kg, intraperitoneally) or sodium orthovanadate (5, 10, and 20 mg/kg, intraperitoneally) was continued during the morphine treatment procedure. Administration of SJA 7019 as well as the sodium orthovanadate dose-dependently attenuated the naloxone-induced morphine withdrawal syndrome. Neither SJA 7019 nor sodium orthovanadate significantly affected locomotor activity or morphine-induced antinociception. Therefore, it may be concluded that treatment with SJA 7019 or sodium orthovanadate during the morphine exposure period attenuated the development of physiological dependence on morphine, possibly through mechanisms linked to activation of tyrosine phosphatase and calpain.