In contrast to previous reports that repeated treatment with morphine rapidly develops tolerance to its analgesic effect, recent clinical findings have shown that morphine did not develop tolerance when used for the palliative of cancer pain. To elucidate such discrepancies, development of tolerance to morphine and U-50,488H, μ- and κ-opioid receptor agonists, respectively, given daily subcutaneously (s.c.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.), and, DPDPE, a selective δ-opioid receptor agonist given i.c.v. and i.t., was investigated by both tail-pinch (TP) method for phasic pain and formalin (FL) test for persistent pain stimulation, from the view of differences in pain types between cancer pain and phasic pain stimulation in the test screening for analgesics.
Daily injection of morphine as well as U-50,488H resulted in the gradual loss of analgesic effect, indicating the development of tolerance to the effect in the TP test by any route of administration; however
, in the FL test, both compounds given s.c. and i.c.v. did not develop tolerance whereas tolerance developed by i.t. administration, supporting above hypothesis that tolerance to analgesic effect of morphine against tonic pain such as cancer pain would be hard to develop. On the other hand, DPDPE given i.c.v. and i.t. easily developed tolerance in both tests. Thus, common mechanisms possibly underlie in the development of tolerance to the suppression of tonic pain by these μ- and κ-opioid receptor agonists, and advantageous clinical use of μ- and κ-agonists but not δ-opioid type is proposed. Additionally, both supraspinal and spinal sites are likely to participate in the development of tolerance to these opioids in the phasic pain, whereas supraspinal site is rather important for the disability of development of tolerance to the suppressive effect of morphine and U-50,488H on the tonic pain stimulation. An anxiolytic drug diazepam also suppressed formalin pain responses. The clinical findings that emotional factors such as anxiety, fear and despair play roles in the production and intensities of chronic pain, are therefore, firstly evidenced by this animal experiment. Less