Sex, Stress and Immunity in the Acute to Chronic Pain Transition

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Arthralgia broadly impacts quality of life because of joint dysfunction and associated pain. Current therapeutics improve management of the arthritic joint but may not satisfactorily address the associated pain. The K/BxN serum transfer model of arthritis produces a long lasting, but reversible inflammation of the joint in mice accompanied by an early onset allodynia that surprisingly persists long after the resolution of inflammatory indices. In the early phase of the model, pain behavior responds to nonsteroidal anti-inflammatory drugs (NSAIDs) and agents that block spinal sensitization (e.g. Gabapentin), while in the post-inflammatory late phase, pain only responds to the latter agents. This behavioral profile is accompanied by a persistent activation of dorsal horn microglia and the appearance of activation transcription factor 3 (ATF3), a marker of afferent injury in the dorsal root ganglia (DRG), in males and females, suggesting a transition in both sexes from an inflammatory to a neuropathic phenotype. Unexpectedly, the female, despite evidence of nerve injury, does not display a comparable late phase pain state. Pharmacological studies and studies with mutant mice have revealed several issues. 1) Transition to a neuropathic phenotype is modulated by spinal Toll-like receptor 4 (TLR4) signaling and T and/or B cells evidenced by resolution of pain in relevant knock out strains. In females that lack T and B cells, resolution of allodynia is largely unaffected. 2) Our work indicates that TLR4 signaling, largely through MyD88 is associated with concurrent activation of proinflammatory (TNF) signaling in males leading to a persistent post inflammatory neuropathic pain state. 3) TLR4 also signals though TRIF and interferon (IFN), which we found to attenuate the algesic effects of TLR4-MyD88 signaling. We speculate that this component accounts for the lack of a late phase allodynia in the female. 4) Based on current evidence, we argue that with persistent, but reversible inflammation, sprouting and neuroma like structures in primary afferents and postganglionic sympathetic efferents occur at the peripheral terminals of the joint and the dorsal root ganglion of the K/BxN male and female. This sprouting is driven by TLR4, which activates inflammatory cells and DRG satellite cells to release growth factors, which trigger/sustain sprouting and promote migration of nerve fibers into the DRG and spinal cord. 5) Involvement of spinal TLR4 in pain processing was suggested to be male specific, and females to preferentially use adaptive immune cells (T/B lymphocytes). We believe however, that both sexes use adaptive immune cells and TLR4 signaling, but to varying degrees. The effects of sex on this transition and the underlying sprouting have not hitherto been characterized. Specifically, these studies using the K/BxN model in males and females will characterize time dependent changes in pain, sprouting (afferent and sympathetic in DRG and ankle), inflammatory cell migration into DRG and spinal cord, glial activation and the role played by sex, TLR4 signaling and T/B cells in these endpoints.