Regulation of spinal neuroimmune responses by prolonged morphine treatment in a rat model of cancer induced bone pain.

Cancer induced bone pain (CIBP) is a major clinical problem. Although opioids remain the principal axis in drug therapies for CIBP, their sustained application is known to induce cellular and molecular adaptations including enhanced neuroimmune reactivity. This is generally characterized by glial activation and proinflammatory cytokine production which frequently results in pharmacological tolerance. This research was performed to investigate spinal neuroimmune responses after prolonged systemic morphine treatment in a rat model of CIBP. The model was established using a unilateral intra-tibia injection of Walker 256 mammary gland carcinoma cells. Subcutaneous morphine was repeatedly administered from postoperative days 14 to 19. Mechanical allodynia to von Frey filaments and ambulatory pain scores were recorded to investigate changes of nociceptive behaviors. Spinal glial activation was detected by immunohistochemistry and real-time PCR; the production of proinflammatory cytokines (IL-1beta and TNF-alpha) was examined through real-time PCR and ELISA. Results showed that chronic morphine use failed to elicit analgesic tolerance in the rat CIBP model. Moreover, the treatment had no significant influence on the activated spinal glia morphology, cell density and expression of special cytomembrane markers, whereas it significantly down-regulated the local proinflammatory cytokine production at the mRNA and protein level. Collectively, these data suggest that chronic morphine treatment in CIBP is not concomitant with pharmacological tolerance, at least partially because the treatment fails to amplify spinal neuroimmune responses.

Evaluation of side effects through selective ablation of the mu opioid receptor expressing descending nociceptive facilitatory neurons in the rostral ventromedial medulla with dermorphin-saporin.

Descending facilitation from the rostral ventromedial medulla (RVM) contributes to some pathological pain states. The intra-RVM microinjection with dermorphin-saporin could specifically abolish this facilitation in rodent models by selectively ablating the RVM neurons expressing mu opioid receptors. Thus, this targeted lesion may be an alternative mechanism-based approach for intractable pain. This research was performed to investigate potential side effects after a single intra-RVM application of dermorphin-saporin in rats. Results showed though some acute cardiovascular signs were observed with dermorphin-saporin, the treatment exhibited no long-lasting significant influence on some physiological functions for up to 3-month observation period, including normal sensory function, locomotor activity, ingestive behaviors, body weight, rectal temperature, respiratory rate, heart rate, systolic blood pressure, cardiac structure and function. Moreover, there were only mild microglial responses on day 7 post-microinjection, while no significant increase in the immunostaining of astrocytes and no noticeable up-regulation in the production of proinflammatory cytokines were detected in the RVM treated with dermorphin-saporin. Taken together, these data would suggest that this selective ablation of mu opioid receptor bearing descending facilitatory neurons in the RVM with dermorphin-saporin did not elicit the long-standing evident adverse toxicity in terms of some physiological parameters and neurochemical alterations we determined, plausibly providing us a safe and reliable approach to treat some intractable pain.