Investigation of tolerance to chronic intrathecal morphine infusion in the rat.

Rats received chronic subcutaneous or intrathecal infusions of either saline or 25 micrograms/microliter/hr or 50 micrograms/microliter/hr of morphine sulfate. During five days of infusion individual groups of rats were assessed on either the nociceptive tail flick or hot plate test. After the infusions, the analgesic effects of either subcutaneous or intrathecal morphine test doses were evaluated. Tolerance developed to the analgesic effect of both subcutaneous and intrathecal morphine infusions on the tail flick test. Subcutaneously infused rats were also tolerant to a subcutaneous morphine challenge on this test. However, intrathecally infused rats were not tolerant to either the subcutaneous or intrathecal challenge. In contrast to these results, rats tested on the hot plate were not analgesic in response to either subcutaneous or intrathecal morphine infusions. However, these rats were tolerant when challenged with either subcutaneous or intrathecal morphine. The results are discussed in terms of the relative contribution of spinal and supraspinal sites to opiate tolerance, and the possibility that tolerance does not develop to the antinociceptive effect of spinal morphine on spinally mediated reflexes.