Pain
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Inhibition of voltage-gated calcium (CaV) channels is a potential therapy for many neurological diseases including chronic pain. Neuronal CaV1/CaV2 channels are composed of α, β, γ and α2δ subunits. The β subunits of CaV channels are cytoplasmic proteins that increase the surface expression of the pore-forming α subunit of CaV. ⋯ IPPQ was antinociceptive in naive animals and reversed allodynia and hyperalgesia in models of acute (postsurgical) and neuropathic (spinal nerve ligation, chemotherapy- and gp120-induced peripheral neuropathy, and genome-edited neuropathy) pain. IPPQ did not cause akinesia or motor impairment, a common adverse effect of CaV2.2 targeting drugs, when injected into the brain. IPPQ, a quinazoline analog, represents a novel class of CaV2.2-targeting compounds that may serve as probes to interrogate CaVα-CaVβ function and ultimately be developed as a nonopioid therapeutic for chronic pain.
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Migraine encompasses a broader spectrum of sensory symptoms than just headache. These "other" symptoms, eg, sensory phobias, cognitive and mood changes, allodynia, and many others indicate an altered sensitivity to sensory input which can be measured, in principle, by quantifying sensory threshold changes longitudinally over time. Photophobia, for example, can be quantified by investigating the discomfort thresholds towards the luminance of light. ⋯ In summary, there is evidence in the literature that migraine could be understood as a periodic sensory dysregulation originating from the brain. Nevertheless, the interstudy discrepancy is still high due to different study designs and a lack of focus on distinct migraine phases. Further well-designed and harmonized studies with an emphasis on the cyclic changes still need to be conducted.
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Although several studies have found that chronic pain is characterized by increased cross-network connectivity between salience network, sensorimotor network, and default mode network (DMN), a large sample-size investigation allowing for a more reliable evaluation of somatotopic specificity and subgroup analyses with linkage to clinical pain intensity has been lacking. We enrolled healthy adults and a large cohort of patients (N = 181) suffering from chronic low back pain (cLBP). To specifically link brain connectivity with clinical pain intensity, patients were scanned at baseline and after performing physical maneuvers that exacerbated pain. ⋯ Hence, increased information transfer between salience processing regions, particularly anterior insula, and DMN may be strongly influenced by pain catastrophizing. Increased information transfer between the salience network and S1 likely plays an important role in shifting nociceptive afference away from self-referential processing, reallocating attentional focus, and affective coding of nociceptive afference from specific body areas. These results demonstrate S1 somatotopic specificity for cross-network connectivity in encoding clinical back pain and moderating influence of catastrophizing for DMN/insula connectivity.
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Diffuse noxious inhibitory controls (DNICs) is a pain-inhibits-pain phenomenon demonstrated in humans and animals. Diffuse noxious inhibitory control is diminished in many chronic pain states, including neuropathic pain. The efficiency of DNIC has been suggested to prospectively predict both the likelihood of pain chronification and treatment response. ⋯ Systemic application of nor-binaltorphimine, a kappa opioid antagonist, did not ameliorate SNL-induced hyperalgesia but reversed loss of the behavioral DNIC response. Microinjection of nor-binaltorphimine into the right central amygdala (RCeA) of SNL rats did not affect baseline thresholds but restored DNIC both behaviorally and electrophysiologically. Cumulatively, these data suggest that net enhanced descending facilitations may be mediated by kappa opioid receptor signaling from the right central amygdala to promote diminished DNIC after neuropathy.