The Journal of neuroscience : the official journal of the Society for Neuroscience
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The dynamic interaction between ascending spinocortical nociceptive signaling and the descending control of the dorsal horn (DH) by brain regions such as the periaqueductal gray matter (PAG) plays a critical role in acute and chronic pain. To noninvasively investigate the processing of nociceptive stimuli in humans, previous fMRI studies either focused exclusively on the brain or, more recently, on the spinal cord. However, to relate neuronal responses in the brain to responses in the spinal cord and to assess the functional interplay between both sites in normal and aberrant conditions, fMRI of both regions within one experiment is necessary. ⋯ Using a parametric pain paradigm with thermal stimulation to the left radial forearm, we observed BOLD responses in the ipsilateral DH of the spinal segment C6 and corresponding neuronal responses in typical pain-processing brain regions. Based on correlations of adjusted time series, we are able to reveal functional connectivity between the spinal C6-DH and the thalamus, primary somatosensory cortex, bilateral insula, bilateral striatum, and key structures of the descending pain-modulatory system such as the PAG, the hypothalamus, and the amygdala. Importantly, the individual strength of the spinal-PAG coupling predicted individual pain ratings highlighting the functional relevance of this system during physiological pain signaling.
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Nerve injury is associated with microvascular disturbance; however, the role of the vascular system has not been well characterized in the context of neuropathic pain. Furthermore, ischemia is thought to play a role in a number of neuropathic pain conditions, and yet the role of hypoxia has also not been characterized in neuropathic pain conditions. In this study, we observed the presence of persistent endoneurial hypoxia in a mouse model of traumatic peripheral nerve injury, causing painful mononeuropathy. ⋯ Physiological antagonism of hypoxia with hyperbaric oxygen alleviated mechanical allodynia in nerve-injured animals. These results suggest that hypoxia and the Na(+)/K(+) ATPase ion transporter may be a novel mechanistic target for the treatment of neuropathic pain. In addition, the findings support the possibility of using hypoxia activated pro-drugs to localize treatments for neuropathic pain and nerve injury to injured nerves.
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Melanin-concentrating hormone (MCH) regulates vital physiological functions, including energy balance and sleep. MCH cells are thought to be GABAergic, releasing GABA to inhibit downstream targets. However, there is little experimental support for this paradigm. ⋯ Interestingly, this led to a feedforward inhibition that depressed LS firing by a robust secondary GABA release. This study presents a circuit analysis between MCH and LS neurons and confirms their functional connection via monosynaptic and polysynaptic pathways. Our findings indicate that MCH neurons are not exclusively GABAergic and reveal a glutamate-mediated, feedforward mechanism that inhibits LS cells.
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Clearing cellular debris after brain injury represents an important mechanism in regaining tissue homeostasis and promoting functional recovery. Triggering receptor expressed on myeloid cells-2 (TREM2) is a newly identified receptor expressed on microglia and is thought to phagocytose damaged brain cells. The precise role of TREM2 during ischemic stroke has not been fully understood. ⋯ TREM2-Fc fusion protein pulled down nucleic acids from ischemic brain lysate. These findings establish the relevance of TREM2 in the phagocytosis of the infarcted brain and emphasize its role in influencing neurological outcomes following stroke. Further, nucleic acids may be one potential ligand of TREM2 in brain ischemia.
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A single nucleotide polymorphism (SNP) in the human μ-opioid receptor gene (OPRM1 A118G) has been widely studied for its association in drug addiction, pain sensitivity, and, more recently, social behavior. The endogenous opioid system has been shown to regulate social distress and reward in a variety of animal models. However, mechanisms underlying the associations between the OPRM1 A118G SNP and these behaviors have not been clarified. ⋯ These findings led us to test the role of endogenous opioids in the A112G mice. We demonstrate that the increase in social affiliation in G carriers is blocked by pretreatment with naloxone. Together, these data suggest a mechanism involving altered hedonic state and neural activation as well as altered endogenous opioid tone in the differential response to aversive and rewarding social stimuli in G-allele carriers.