Front Cell Neurosci
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Front Cell Neurosci · Jan 2014
ReviewPeroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines?
Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain) is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. ⋯ Experimental evidence suggests a connection between the pain ameliorating effects of PPAR agonists and suppression of inflammatory gene expression, including chemokines. In early clinical research, one PPARα agonist, palmitoylethanolamide (PEA), shows promise in relieving chronic pain. If this link can be better established, PPAR agonists may represent a new drug therapy for neuropathic pain.
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Front Cell Neurosci · Jan 2014
ReviewNeuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain.
The development of neuropathic pain in response to peripheral nerve lesion for a large part depends on microglia located at the dorsal horn of the spinal cord. Thus the injured nerve initiates a response of microglia, which represents the start of a cascade of events that leads to neuropathic pain development. For long it remained obscure how a nerve injury in the periphery would initiate a microglia response in the dorsal horn of the spinal cord. ⋯ Recent results obtained in transgenic animals clearly show that microglia in vivo do not express CCR2 but that peripheral myeloid cells and neurons do. This suggests that CCL2 expressed by injured dorsal root neurons does not act as neuron-microglia signal in contrast to CCL21. Instead, CCL2 in the injured dorsal root ganglia (DRG) may act as autocrine or paracrine signal and may stimulate first or second order neurons in the pain cascade and/or attract CCR2-expressing peripheral monocytes/macrophages to the spinal cord.
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Neuropathic pain, a debilitating pain condition, is a common consequence of damage to the nervous system. Neuropathic pain is often resistant to currently available analgesics. A growing body of evidence indicates that spinal microglia react and undergo a series of changes that directly influence the establishment of neuropathic pain states. ⋯ Importantly, inhibiting the function or expression of P2X4Rs and P2X4R-regulating molecules suppresses the aberrant excitability of dorsal horn neurons and neuropathic pain. These findings indicate that P2X4R-positive microglia are a central player in mechanisms for neuropathic pain. Thus, microglial P2X4Rs are a potential target for treating the chronic pain state.
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Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. ⋯ For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders.