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Hematogenous macrophages remove myelin debris from injured peripheral nerves to provide a micro-environment conducive to axonal regeneration. Previously, we observed that injured peripheral nerves from Beta-site APP Cleaving Enzyme 1 (BACE1) knockout (KO) mice displayed earlier influx of and enhanced phagocytosis by macrophages when compared to wild-type (WT) mice. These observations suggest that BACE1 might regulate macrophage influx into distal stumps of injured nerves. To determine through which pathway BACE1 influences macrophage influx, we used a mouse inflammation antibody array to assay the expression of inflammation-related proteins in injured nerves of BACE1 KO and WT mice. The most significant change was in expression of tumor necrosis factor receptor 1 (TNFR1) in the distal stump of injured BACE1 KO nerves. Western blotting of protein extracts confirmed increased expression of TNFR1 and its downstream transcriptional factor NFκB in the BACE1 KO distal stumps. Additionally, treatment of WT mice with a BACE1 inhibitor resulted in increased TNFR1 expression and signaling in the distal stump of injured nerves. Exogenous TNFα increased nuclear translocation of p65 NFκB in BACE1 KO tissue and cultured fibroblasts compared with control WT. BACE1 regulates TNFR1 expression at the level of gene expression and not through proteolytic processing. The accelerated macrophage influx in injured nerves of BACE1 KO mice correlates with increased expression and signaling via TNFR1, indicating a link between BACE1 activity and TNFR1 expression/signaling that might contribute to repair of the injured nervous system.

Men are typically reported to have higher pain thresholds than women. Gonadal hormones, particularly testosterone for males, may contribute to this effect. This study tested whether changes in the male hormonal milieu early or late in development alter the inflammatory pain induced by carrageenan (CARR, 3%, intraarticular). Male rats were either gonadectomized or sham gonadectomized neonatally. Once adults, the same rats underwent either sham surgery or gonadectomy, and received a testosterone or oil implant. After baseline testing two weeks later, animals were tested in response to mechanical and thermal stimulation following CARR-induced inflammation and injection of saline, 1 mg/kg, or 5 mg/kg morphine. Hormone alterations did not affect baseline responses, but CARR induced mechanical and thermal hyperalgesia in the injured limb. Gonadectomy in adult males injected with saline enhanced inflammation-induced sensitivity to mechanical but not thermal stimulation and the effect was reversed by testosterone. After inflammation, saline-treated males gonadectomized neonatally displayed lower mechanical threshold than control sham animals but this effect was not reversed by testosterone. Both doses of morphine increased mechanical and thermal thresholds. However, compared with the control group, 1 mg/kg morphine was equally effective in reducing mechanical hyperalgesia among groups of animals gonadectomized as adults, but less effective in males gonadectomized neonatally. The results suggest that in males: 1. the antihyperalgesic effect of testosterone (or its metabolites) in CARR-induced inflammation is established during development and maintained by circulating levels of testosterone in adulthood; 2. the nociception-related interaction between the opioid and gonadal systems influences the sensitivity to mechanical stimuli and is likely established during the period of sexual differentiation.

Homeostasis, an organisms' tendency to maintain a healthy balance of the physiological state of the body, is necessary for survival. Hunger induces a motivational state to consume food. Recently, pain has been referred to as a homeostatic emotion similar to hunger or thirst in that animals are motivated to respond in a certain way that may increase their chance of survival. Therefore, the purpose of the present experiment was to examine behavior in rodents during two competing homeostatic/motivational drives (i.e., hunger and formalin pain). During the first phase of the formalin test, animals displayed typical responsiveness to the inflammatory condition and completed fewer chains for food reinforcement as compared to the baseline session. However, during the second phase of the formalin test, animals showed decreased nociceptive behavior compared to formalin-injected animals that were not trained in the operant conditioning paradigm. During this phase, the trained animals exhibited maximal responsiveness for food reinforcement. These results demonstrate that the engagement of behaviors reflecting motivational drives to restore homeostasis depends on the intensity or degree of imbalance of the competing drives. More specifically, animals are motivated to attend to one state of imbalance at a time.