phenanthrenes and Chronic-Pain

Chronic pain and depression frequently coexist in clinical setting, and current clinical treatments for this comorbidity have shown limited efficacy. Triptolide (T10), an active component of Tripterygium wilfordii Hook F., has been demonstrated to exert strong analgesic activities in experimental pain models, but whether it possesses anti-depressive actions remains unknown. Using a depression comorbidity of chronic pain rat model induced by spinal nerve ligation (SNL), we investigated the potency of T10 for the treatment of comorbid depression in comparison with a widely used antidepressant, fluoxetine (FLX). Concomitant neuroinflammation changes were also examined in the hippocampus. The results showed that prophylactic and reversal treatments with T10 dose-dependently (30, 100, 300μg/kg) inhibited the depression-like behaviors (DLB) assessed by the forced swim test, sucrose preference test and body weight measurement. The anti-depressive efficacy of T10 at 300μg/kg was significantly stronger than that of FLX at 18mg/kg. T10 at all three doses exhibited more efficient analgesic effects than FLX at 18mg/kg. The combined application of T10 with FLX markedly augmented the effects of T10 or FLX per se, with the facilitating effects of T10 at 30μg/kg being most prominent. In addition, nerve injury caused the activation of microglia and p38 MAPK, the upregulation of IL-1β and TNF-α as well as the downregulation of IL-10 in the hippocampus at postoperative week (POW) 3. These neuroinflammatory responses were reversed by subchronic treatment with T10. Taken together, these results demonstrate that T10 possesses potent anti-depressive function, which is correlated with its immunoregulation in the hippocampus. The combination of a low dose of T10 with FLX may become a more effective medication strategy for the treatment of comorbid depression and chronic pain.

Topics: Analgesics; Animals; Antidepressive Agents; Behavior, Animal; Chronic Pain; Depression; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Drug Therapy, Combination; Encephalitis; Epoxy Compounds; Fluoxetine; Hippocampus; Hyperalgesia; Inflammation Mediators; Male; Microglia; Phenanthrenes; Rats, Sprague-Dawley

Triptolide is a potent immunosuppressive drug capable of inhibiting T cell activation and proliferation. Recent studies show that T cells play an important role in neuropathic pain following nerve injury in rats. In this study, we investigated the effect of triptolide on T cell activation and development of neuropathic pain. Neuropathic pain by chronic constriction injury (CCI) was induced by loose ligation of the sciatic nerve in Sprague-Dawley rats. Triptolide (5 or 10 μg/kg) or vehicle (DMSO) was administered intrathecally after surgery for 7 days (n=8 per group). The right hind paw withdrawal threshold to von Frey filament stimuli and withdrawal latency to radiant heat were determined before and after the surgery (days 0 to 7). NF-κB activation and pro-inflammatory cytokine (TNF-α and IL-2) expression were determined by ELISA, Western blot, and real time-PCR. CCI of the sciatic nerve induced mechanical allodynia and thermal hyperalgesia in these rats. Intrathecal triptolide (5 and 10 μg/kg) suppressed the development of allodynia and thermal hyperalgesia. It also inhibited CCI-induced inflammation and T cell activation, by decreasing spinal cord TNF-α, IL-2 and NF-κB p65 levels. Motor dysfunction was not observed after triptolide treatment. In the present study, we demonstrated the suppressive effect of triptolide on the development of neuropathic pain. Therefore, triptolide could be a promising immunosuppressive agent in the treatment of neuropathic pain. Further studies are required to examine the safety of intrathecal triptolide for clinical application.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chronic Pain; Diterpenes; Epoxy Compounds; Hyperalgesia; Interleukin-2; Lymphocyte Activation; Neuralgia; Phenanthrenes; Rats; Spinal Cord Injuries; T-Lymphocytes; Transcription Factor RelA; Tumor Necrosis Factor-alpha