Females greatly outnumber males as sufferers of chronic pain. Although social and psychological factors certainly play a role in the differences in prevalence and incidence, biological differences in the functioning of the immune system likely underlie these observed effects. This Review examines the current literature on biological sex differences in the functioning of the innate and adaptive immune systems as they relate to pain experience. With rodent models, we and others have observed that male mice utilize microglia in the spinal cord to mediate pain, whereas females preferentially use T cells in a similar manner. The difference can be traced to differences in cell populations, differences in suppression by hormones, and disparate cellular responses in males and females. These sex differences also translate into human cellular responses and may be the mechanism by which the disproportionate chronic pain experience is based. Recognition of the evidence underlying sex differences in pain will guide development of treatments and provide better options for patients that are tailored to their physiology. © 2016 Wiley Periodicals, Inc.

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.

BACKGROUND-Outcomes in children and adolescents with recurrent or progressive highgrade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric highgrade gliomas are largely immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue.

AbstractBackground and aimsObesity is a significant health concern in the Western world and the presence of comorbid conditions suggests an interaction. The overlapping distributions of chronic pain populations and obesity suggests that an interaction may exist. Poor quality diet (high carbohydrates, saturated fats, omega-6 polyunsaturated fatty acids) can lead to increased adiposity which can activate immune cells independent of the activating effect of the diet components themselves. This dual action can contribute to chronic inflammation that may alter susceptibility to chronic pain and prolong recovery from injury. However, traditional examinations of diet focus on high-fat diets that often contain a single source of fat, that is not reflective of an American diet. Thus, we examined the impact of a novel human-relevant (high-carbohydrate) American diet on measures of pain and inflammation in rats, as well as the effect on recovery and immune cell activation.MethodsWe developed a novel, human-relevant Standard American Diet (SAD) to better model the kilocalorie levels and nutrient sources in an American population. Male and female rats were fed the SAD over the course of 20 weeks prior to persistent inflammatory pain induction with Complete Freund’s Adjuvant (CFA). Mechanical and thermal sensitivity were measured weekly. Spontaneous pain, open field locomotion and blood glucose levels were measured during diet consumption. Body composition was assessed at 20 weeks. Following full recovery from CFA-induced hypersensitivity, blood was analyzed for inflammatory mediators and spinal cords were immunohistochemically processed for microglial markers.ResultsChronic consumption of the SAD increased fat mass, decreased lean mass and reduce bone mineral density. SAD-fed rats had increased leptin levels and pro-inflammatory cytokines in peripheral blood serum. Following CFA administration, mechanical sensitivity was assessed and recovery was delayed significantly in SAD-fed animals. Sex differences in the impact of the SAD were also observed. The SAD increased body weight and common T-cell related inflammatory mediators in female, but not male, animals. In males, the SAD had a greater effect on bone mineral density and body composition. Long-term consumption of the SAD resulted in elevated microglial staining in the dorsal horn of the spinal cord, but no sex differences were observed.ConclusionsWe demonstrate the negative effects of an American diet on physiology, behavior and recovery from injury. SAD consumption elevated pro-inflammatory mediators and increased microglial activation in the spinal cord. While there were sex differences in weight gain and inflammation, both sexes showed prolonged recovery from injury.ImplicationsThese data suggest that poor quality diet may increase susceptibility to chronic pain due to persistent peripheral and central immune system activation. Furthermore, consumption of a diet that is high in carbohydrates and omega-6 polyunsaturated fatty acid is likely to lead to protracted recovery following trauma or surgical procedures. These data suggest that recovery of a number of patients eating a poor quality diet may be expedited with a change in diet to one that is healthier.

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 (PGE 2 ) response was blunted. However, when these neurons were lesioned after the induction of priming, they had no effect on the PGE 2 response, 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 PGE 2 injection 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.

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Malignant tumors of the central nervous system (CNS) continue to be a leading cause of cancerrelated mortality in both children and adults. Traditional therapies for malignant brain tumors consist of surgical resection and adjuvant chemoradiation; such approaches are often associated with extreme morbidity. Accordingly, novel, targeted therapeutics for neoplasms of the CNS, such as immunotherapy with oncolytic engineered herpes simplex virus (HSV) therapy, are urgently warranted. Herein, we discuss treatment challenges related to HSV virotherapy delivery, entry, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Extinction of Pavlovian conditioned fear in humans is a popular paradigm often used to study learning and memory processes that mediate anxiety-related disorders. Fear extinction studies often only pair the conditioned stimulus (CS) and unconditioned stimulus (UCS) on a subset of acquisition trials (i.e., partial reinforcement/pairing) to prolong extinction (i.e., partial reinforcement extinction effect; PREE) and provide more time to study the process. However, there is limited evidence that the partial pairing procedures typically used during fear conditioning actually extend the extinction process, while there is strong evidence these procedures weaken conditioned response (CR) acquisition. Therefore, determining conditioning procedures that support strong CR acquisition and that also prolong the extinction process would benefit the field. The present study investigated 4 separate CS-UCS pairing procedures to determine methods that support strong conditioning and that also exhibit a PREE. One group (C-C) of participants received continuous CS-UCS pairings; a second group (C-P) received continuous followed by partial CS-UCS pairings; a third group (P-C) received partial followed by continuous CS-UCS pairings; and a fourth group (P-P) received partial CS-UCS pairings during acquisition. A strong skin conductance CR was expressed by C-C and P-C groups but not by C-P and P-P groups at the end of the acquisition phase. The P-C group maintained the CR during extinction. In contrast, the CR extinguished quickly within the C-C group. These findings suggest that partial followed by continuous CS-UCS pairings elicit strong CRs and prolong the extinction process following human fear conditioning.