Spinal antagonism of tolerance and dependence induced by systemically administered morphine

We observed that the spinal cord of rats was involved in development of tolerance and dependence to morphine that was administered systemically by s.c. morphine-pellet implantation. Rats, surgically fitted with intrathecal catheters, were injected intrathecally (i.t.) with saline or 2.4 nmol beta-chlornaltrexamine (beta-CNA), an irreversible opiate antagonist. Twenty-four h later, animals were implanted s.c. with either placebo or morphine pellets. Seventy-two h after implanting pellets, development of tolerance or dependence was assessed. Control animals implanted with morphine pellets became tolerant to analgesia induced by i.p. injections of morphine as determined by the use of tail flick and hot plate analgesic assays. beta-CNA pretreatment antagonized the effects of i.p. injections of morphine and blocked development of tolerance in morphine-implanted animals. Dependence was assessed by observing several characteristic signs of precipitated withdrawal. Treatment with beta-CNA before morphine treatment antagonized naloxone-induced expression of withdrawal for all signs observed, except weight loss. We conclude that the spinal cord plays a significant role in development of tolerance and dependence induced by systemically administered opiates.