Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes

Aim: To investigate the mechanisms underlying the anti-nociceptive effect of minocycline on bone cancer pain (BCP) in rats. Methods: A rat model of BCP was established by inoculating Walker 256 mammary carcinoma cells into tibial medullary canal. Two weeks later, the rats were injected with minocycline (50, 100 mu g, intrathecally; or 40, 80 mg/kg, ip) twice daily for 3 consecutive days. Mechanical paw withdrawal threshold (PWT) was used to assess pain behavior. After the rats were euthanized, spinal cords were harvested for immunoblotting analyses. The effects of minocycline on NF-kappa B activation were also examined in primary rat astrocytes stimulated with IL-1 beta in vitro. Results: BCP rats had marked bone destruction, and showed mechanical tactile allodynia on d 7 and d 14 after the operation. Intrathecal injection of minocycline (100 mu g) or intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced mechanical tactile allodynia. Furthermore, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of GFAP (astrocyte marker) and PSD95 in spinal cord. Moreover, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of NF-kappa B, p-IKK alpha and I kappa B alpha in spinal cord. In IL-1 beta-stimulated primary rat astrocytes, pretreatment with minocycline (75, 100 mu mol/L) significantly inhibited the translocation of NF-kappa B to nucleus. Conclusion: Minocycline effectively alleviates BCP by inhibiting the NF-kappa B signaling pathway in spinal astrocytes.