Induction of tolerance and withdrawal in rats receiving morphine in the spinal subarachnoid space

Rats implanted with chronic catheters in the spinal subarachnoid space were given twice daily injections for 7 days of morphine sulfate, either intrathecally into the lumbar subarachnoid space (15 or 50 microng) or i.p. (20 mg/kg). The development of tolerance, as manifested in a reduction of the analgetic efficacy of these injections on the hot plate and tail flick, occurred in a dose dependent fashion over a period of 7 days. At this time, injections of i.p. morphine into animals which had received spinal morphine and vice versa revealed the existence of a two way cross tolerance between spinal and systemically administered morphine. Injection of naloxone into the spinal cord of animals exposed to i.p. morphine or conversely, i.p. naloxone in animals tolerant to intrathecal morphine, yielded a hyperreflexia and extreme sensitivity to handling. Other signs commonly observed in percipitated withdrawal, however, such as wet shakes and weight loss, were not observed.