Chronic pain is a significant problem worldwide and is the most common disability in the United States. It is well known that the immune system plays a critical role in the development and maintenance of many chronic pain conditions. The involvement of the immune system can be through the release of autoantibodies, in the case of rheumatoid arthritis, or via cytokines, chemokines, and other inflammatory mediators (i.e. substance P, histamine, bradykinin, tumor necrosis factor, interleukins, and prostaglandins). Immune cells, such as T cells, B cells and their antibodies, and microglia are clearly key players in immune-related pain. The purpose of this review is to briefly discuss the immune system involvement in pain and to outline how it relates to rheumatoid arthritis, osteoarthritis, fibromyalgia, complex regional pain syndrome, multiple sclerosis, and diabetic neuropathy. The immune system plays a major role in many debilitating chronic pain conditions and we believe that animal models of disease and their treatments should be more directly focused on these interactions.

The EGFR belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation, and tissue regeneration. In the present study, we have demonstrated a role for EGFR and its natural ligand, epiregulin (EREG), in pain processing. We show that inhibition of EGFR with clinically available compounds strongly reduced nocifensive behavior in mouse models of inflammatory and chronic pain. EREG-mediated activation of EGFR enhanced nociception through a mechanism involving the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9. Moreover, EREG application potentiated capsaicin-induced calcium influx in a subset of sensory neurons. Both the EGFR and EREG genes displayed a genetic association with the development of chronic pain in several clinical cohorts of temporomandibular disorder. Thus, EGFR and EREG may be suitable therapeutic targets for persistent pain conditions.

Chronic pain is highly prevalent in the United States, impacting 28.4% of the adult population, or 69.6 million people, as of 2016. Chronic pain is often associated with anxiety, depression, and restrictions in mobility and daily activities, substantially reducing quality of life. Analgesics, especially opioids, are one of the primary pharmaceutical treatment methods for chronic pain. However, prescription opioid misuse and abuse has become increasingly prevalent and concerning, prompting the need for research into alternative treatment methods which avoid the side effects of traditional treatments. Chronic pain is, in part, thought to be the result of oxidative stress and inflammation, and clinical research has indicated links between these conditions and diet. Thus, dietary interventions are a particularly promising therapeutic treatment for chronic pain, with numerous studies suggesting that diet has a noticeable effect on pain as far down as the cellular level. In this review article, data from a number of clinical trials assessing the effect of three diets—antioxidant-rich, low-carbohydrate, and Mediterranean—on oxidative stress and inflammation is compiled and discussed in the context of chronic pain. Clinical data suggests that low-carbohydrate diets and Mediterranean diets both are especially promising dietary interventions.

The mechanisms that lead to the maintenance of chronic pain states are poorly understood, but their elucidation could lead to new insights into how pain becomes chronic and how it can potentially be reversed. We investigated the role of spinal dorsal horn neurons and descending circuitry in plasticity mediating a transition to pathological pain plasticity suggesting the presence of a chronic pain state using hyperalgesic priming. We found that when dorsal horn neurokinin 1 receptor-positive neurons or descending serotonergic neurons were ablated before hyperalgesic priming, IL-6- and carrageenan-induced mechanical hypersensitivity was impaired, and subsequent prostaglandin E2 (PGE₂) response was blunted. However, when these neurons were lesioned after the induction of priming, they had no effect on the PGE₂response, reflecting differential mechanisms driving plasticity in a primed state. In stark contrast, animals with a spinally applied dopaminergic lesion showed intact IL-6- and carrageenan-induced mechanical hypersensitivity, but the subsequent PGE₂injection failed to cause mechanical hypersensitivity. Moreover, ablating spinally projecting dopaminergic neurons after the resolution of the IL-6- or carrageenan-induced response also reversed the maintenance of priming as assessed through mechanical hypersensitivity and the mouse grimace scale. Pharmacological antagonism of spinal dopamine D₁/D₅receptors reversed priming, whereas D₁/D₅agonists induced mechanical hypersensitivity exclusively in primed mice. Strikingly, engagement of D₁/D₅coupled with anisomycin in primed animals reversed a chronic pain state, consistent with reconsolidation-like effects in the spinal dorsal horn. These findings demonstrate a novel role for descending dopaminergic neurons in the maintenance of pathological pain plasticity.