Possible relevance of tolerance to analgesic effect of morphine due to chronic inflammatory pain and the role of lumbar spinal cord in this interaction

It has been reported that morphine tolerance does not develop in the presence of chronic pain. Therefore, this study was conducted to find out whether chronic inflammatory pain is able to eliminate or attenuate the developed tolerance to analgesic effect of morphine and also to investigate the role of lumbar spinal cord as a candidate site for this interaction. Tolerance was induced in adult male NMRI rats using daily injection of morphine at a dose of 20 mg/kg (i.p.) for 4 days, or using daily injection of morphine at a dose of 15 pg/rat (i.t.) for 7 days. Chronic inflammatory pain was induced using 50 µl of 5% formalin, injected into the hind paws. The antinociceptive effect of morphine at a dose of 10 mg/kg on day 5 (for i.p. treated rats) or morphine at a dose of 15 pg/rat on day 8 (for i.t. treared rats) were assessed using tail flick test. The results showed that those animals receiving saline (i.t. or i.p.) have potent analgesia (p<0.001), while animals treated with chronic morphine have only a weak analgesia for i.p. treatment (p<0.05). In addition, animals treated with both repeated morphine and 5% formalin (s.c.) into the hind paw showed potent analgesia (p<0.01). Meanwhile, the developed tolerance was reversed by chronic pain induction in the following days (p<0.01). It is concluded that chronic formalin-induced inflammatory pain, not only could prevent tolerance development, but also is able to reverse the developed tolerance to antinociceptive effect of morphine. Since in i.t.-treated animals, tolerance was induced in lumbar spinal cord level, it can be concluded that chronic formalin-induced inflammatory pain, as a stress (through HPA axis) or as a factor which directly exerts some modulations on pain transmission system, is able to prevent tolerance to analgesic effect of morphine through lumbar spinal cord.