Neuron
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Neuropathic pain and allodynia may arise from sensitization of central circuits. We report a mechanism of disinhibition-based central sensitization resulting from long-term depression (LTD) of GABAergic interneurons as a consequence of TRPV1 activation in the spinal cord. Intrathecal administration of TRPV1 agonists led to mechanical allodynia that was not dependent on peripheral TRPV1 neurons. ⋯ Mechanical hypersensitivity after peripheral nerve injury was attenuated in TRPV1(-/-) mice but not in mice lacking TRPV1-expressing peripheral neurons. Mechanical pain was reversed by a spinally applied TRPV1 antagonist while avoiding the hyperthermic side effect of systemic treatment. Our results demonstrate that spinal TRPV1 plays a critical role as a synaptic regulator and suggest the utility of central nervous system-specific TRPV1 antagonists for treating neuropathic pain.
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The mammalian circadian system, which is comprised of multiple cellular clocks located in the organs and tissues, orchestrates their regulation in a hierarchical manner throughout the 24 hr of the day. At the top of the hierarchy are the suprachiasmatic nuclei, which synchronize subordinate organ and tissue clocks using electrical, endocrine, and metabolic signaling pathways that impact the molecular mechanisms of cellular clocks. ⋯ Disturbances in the communication between the plethora of body clocks can desynchronize the circadian system, which is believed to contribute to the development of diseases such as obesity and neuropsychiatric disorders. This review will highlight the relationship between clocks and metabolism, and describe how cues such as light, food, and reward mediate entrainment of the circadian system.
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After nerve injury maladaptive changes can occur in injured sensory neurons and along the entire nociceptive pathway within the CNS, which may lead to spontaneous pain or pain hypersensitivity. The resulting neuropathic pain syndromes present as a complex combination of negative and positive symptoms, which vary enormously from individual to individual. This variation depends on a diversity of underlying pathophysiological changes resulting from the convergence of etiological, genotypic, and environmental factors. The pain phenotype can serve therefore, as a window on underlying pathophysiological neural mechanisms and as a guide for developing personalized pain medicine.
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Epigenetic processes, such as histone modifications and DNA methylation, have been associated with many neural functions including synaptic plasticity, learning, and memory. Here, we critically examine emerging evidence linking epigenetic mechanisms to the development or maintenance of chronic pain states. Although in its infancy, research in this area potentially unifies several pathophysiological processes underpinning abnormal pain processing and opens up a different avenue for the development of novel analgesics.
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The brain and body respond to potential and actual stressful events by activating hormonal and neural mediators and modifying behaviors to adapt. Such responses help maintain physiological stability ("allostasis"). When behavioral or physiological stressors are frequent and/or severe, allostatic responses can become dysregulated and maladaptive ("allostatic load"). ⋯ As a result, the brain's responses to continued/subsequent stressors are abnormal, and behavior and systemic physiology are altered in ways that can, in a vicious cycle, lead to further allostatic load. Migraine patients are continually exposed to such stressors, resulting in changes to central and peripheral physiology and function. Here we review how changes in brain states that occur as a result of repeated migraines may be explained by a maladaptive feedforward allostatic cascade model and how understanding migraine within the context of allostatic load model suggests alternative treatments for this often-debilitating disease.