Activity-induced muscle pain increases interleukin-1(3 (IL-1(3) release from muscle macrophages and the development of hyperalgesia is prevented by blockade of IL-1(3 in muscle. Brain derived neurotrophic factor (BDNF) is released from sensory neurons in response to IL-1(3 and mediates both inflammatory and neuropathic pain. Thus, we hypothesize that in activity-induced pain, fatigue metabolites combined with IL-1(3 activate sensory neurons to increase BDNF release, peripherally in muscle and centrally in the spinal dorsal horn, to produce hyperalgesia. We tested the effect of intrathecal or intramuscular injection of BDNF-Tropomyosin receptor kinase B (TrkB) inhibitors, ANA-12 or TrkB-Fc, on development of activity-induced pain. Both inhibitors prevented the hyperalgesia when given before or 24hr after induction of the model in male but not female mice. BDNF messenger ribonucleic acid (mRNA) and protein were significantly increased in dorsal root ganglion (DRG) 24hr after induction of the model in both male and female mice. Blockade of IL-1(3 in muscle had no effect on the increased BNDF mRNA observed in the activity-induced pain model, while IL-1(3 applied to cultured DRG significantly induced BDNF expression, suggesting IL-1(3 is sufficient but not necessary to induce BNDF. Thus, fatigue metabolites, combined with IL-1(3, upregulate BDNF in primary DRG neurons in both male and female mice, but contribute to activity-induced pain only in males.
