Alendronate Attenuates Spinal Microglial Activation and Neuropathic Pain

• Alendronate significantly prevented development of chronic constriction injury–induced mechanical/thermal hypersensitivity, after intrathecal and intra-peritoneal administration.
• Chronic constriction injury–induced microglial activation and phosphorylation of p38 in the spinal cord were attenuated by alendronate administration.
• Alendronate downregulated phosphorylated p38 expression and decreased the expression of inflammatory cytokines (tumor necrosis factor α, and interleukins 1β and 6) in lipopolysaccharide-stimulated primary microglia culture.

Many derivatives of bisphosphonates, which are inhibitors of bone resorption, have been developed as promising agents for painful pathologies in patients with bone resorption-related diseases. The mechanism for pain relief by bisphosphonates remains uncertain. Studies have reported that bisphosphonates could reduce central neurochemical changes involved in the generation and maintenance of bone cancer pain. In this study, we hypothesized that bisphosphonates would inhibit spinal microglial activation and prevent the development of hyperalgesia caused by peripheral tissue injury. We investigated the effects of alendronate (a nitrogen-containing bisphosphonate) on the development of neuropathic pain and its role in modulating microglial activation in vivo and in vitro. Intrathecal and intraperitoneal administration of alendronate relieved neuropathic pain behaviors induced by chronic constriction sciatic nerve injury. Alendronate also significantly attenuated spinal microglial activation and p38 mitogen-activated protein kinase (MAPK) phosphorylation without affecting astrocytes. In vitro, alendronate downregulated phosphorylated p38 and phosphorylated extracellular signal regulated kinase expression in lipopolysaccharide-stimulated primary microglia within 1 hour, and pretreatment with alendronate for 12 and 24 hours decreased the expression of inflammatory cytokines (tumor necrosis factor α, and interleukins 1β and 6). These findings indicate that alendronate could effectively relieve chronic constriction sciatic nerve injury–induced neuropathic pain by at least partially inhibiting the activation of spinal microglia and the p38 MAPK signaling pathway.PerspectiveAlendronate could relieve neuropathic pain behaviors in animals by inhibiting the activation of spinal cord microglia and the p38 MAPK cell signaling pathway. Therapeutic applications of alendronate may be extended beyond bone metabolism–related disease.