ABSTRACT
Microglia are important mediators of neuroinflammation, which underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. Here, we investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuates Ca2+ signaling and the production of inflammatory cytokines by proalgesic agonists. Conditional deletion of Orai1 attenuated microglial proliferation in the dorsal horn, spinal cytokine levels, and potentiation of excitatory neurotransmission following peripheral nerve injury. These cellular effects were accompanied by mitigation of pain hyperalgesia in microglial Orai1 knockout mice. A small-molecule Orai1 inhibitor, CM4620, similarly mitigated allodynia in male mice. Unexpectedly, these protective effects were not seen in female mice, revealing sexual dimorphism in Orai1 regulation of microglial reactivity and hyperalgesia. Together, these findings indicate that Orai1 channels are key regulators of the sexually dimorphic role of microglia for the neuroinflammation that underlies neuropathic pain.
Subject(s)
Microglia , Neuralgia , Mice , Male , Female , Animals , Microglia/metabolism , Hyperalgesia/genetics , Neuroinflammatory Diseases , Neuralgia/genetics , Mice, Knockout , Cytokines/metabolism , Spinal Cord , ORAI1 Protein/geneticsABSTRACT
The positive or negative value (valence) of past experiences is normally integrated into neuronal circuits that encode episodic memories and plays an important role in guiding behavior. Here, we show, using mouse behavioral models, that glutamatergic afferents from the ventral tegmental area to the dorsal hippocampus (VTAâDH) signal negative valence to memory circuits, leading to the formation of fear-inducing context memories and to context-specific reinstatement of fear. To a lesser extent, these projections also contributed to opioid-induced place preference, suggesting a role in signaling positive valence as well, and thus a lack of dedicated polarity. Manipulations of VTA terminal activity were more effective in females and paralleled by sex differences in glutamatergic signaling. By prioritizing retrieval of negative and positive over neutral memories, the VTAâDH circuit can facilitate the selection of adaptive behaviors when current and past experiences are valence congruent.
Subject(s)
Hippocampus/physiology , Memory/physiology , Nerve Net/physiology , Ventral Tegmental Area/physiology , Animals , Conditioning, Classical , Dentate Gyrus/drug effects , Dentate Gyrus/physiology , Fear/physiology , Female , Gene Silencing/drug effects , Glutamate Decarboxylase/metabolism , Glutamates/metabolism , Hippocampus/drug effects , Kinetics , Male , Memory/drug effects , Mice, Inbred C57BL , Morphine/pharmacology , Nerve Net/drug effects , Optogenetics , Receptors, N-Methyl-D-Aspartate/metabolism , Sex Characteristics , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Ventral Tegmental Area/drug effects , Vesicular Glutamate Transport Protein 2/metabolismABSTRACT
Chronic pain has been shown to affect up to 60% of patients undergoing surgery for breast cancer. Besides younger age, other risk factors for the development of chronic pain have not been consistent in previous studies. The objective of the current investigation was to detect the prevalence and risk factors for the development of chronic pain after breast cancer surgery by examining a patient population from a tertiary cancer center in the United States. The study was a prospective observational cohort study. Subjects were evaluated at least 6 months after the surgical procedure. Subjects responded to the modified short form Brief pain inventory and the short form McGill pain questionnaire to identify and characterize pain. Demographic, surgery, cancer treatment, and perioperative characteristics were recorded. Propensity matching regression analysis were used to examine risk factors associated with the development of chronic pain. 300 patients were included in the study. 110 reported the presence of chronic pain. Subjects with chronic pain reported median (interquartile range [IQR]) rating of worst pain in the last 24 hours of 4 (2-5) and a median (IQR) rating on average pain in the last 24 hours of 3 (1-4) on a 0-10 numeric rating scale. Independent risk factors associated with the development of chronic pain were age, OR (95% CI) of 0.95 (0.93-0.98) and axillary lymph node dissection, 7.7 (4.3-13.9) but not radiation therapy, 1.05(0.56-1.95). After propensity matching for confounding covariates, radiation was still not associated with the development of chronic pain. Chronic pain after mastectomy continues to have a high prevalence in breast cancer patients. Younger age and axillary lymph node dissection but not radiation therapy are risk factors for the development of chronic pain. Preventive strategies to minimize the development of chronic pain are highly desirable.
