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Neuropathic pain conditions including neuropathic orofacial pain (NOP) are difficult to treat. Contemporary therapeutic agents for neuropathic pain are often ineffective in relieving pain and are associated with various adverse effects. Finding new options for treating neuropathic pain is a major priority in pain-related research. Cannabinoid-based therapeutic strategies have emerged as promising new options. Cannabinoids mainly act on cannabinoid 1 (CB1) and 2 (CB2) receptors, and the former is widely distributed in the brain. The therapeutic significance of cannabinoids is masked by their adverse effects including sedation, motor impairment, addiction and cognitive impairment, which are thought to be mediated by CB1 receptors in the brain. Alternative approaches have been developed to overcome this problem by selectively targeting CB2 receptors, peripherally restricted CB1 receptors and endocannabinoids that may be locally synthesized on demand at sites where their actions are pertinent. Many preclinical studies have reported that these strategies are effective for treating neuropathic pain and produce no or minimal side effects. Recently, we observed that inhibition of degradation of a major endocannabinoid, 2-arachydonoylglycerol, can attenuate NOP following trigeminal nerve injury in mice. This review will discuss the above-mentioned alternative approaches that show potential for treating neuropathic pain including NOP.
Learn More >Hevin, a matricellular protein involved in tissue repair and remodeling, is crucial for initiation and development of excitatory synapses. Besides, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) is an ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS). This study aimed to investigate the correlation between spinal Hevin and AMPA receptors in remifentanil-induced postoperative hyperalgesia in mice.
Learn More >Oxytocin possesses several physiological and social functions, among which an important analgesic effect. For this purpose, oxytocin binds mainly to its unique receptor, both in the central nervous system and in the peripheral nociceptive terminal axon in the skin. However, despite its interesting analgesic properties and its current use in clinics to facilitate labor, oxytocin is not used in pain treatment. Indeed, it is rapidly metabolized, with a half-life in the blood circulation estimated at five minutes and in cerebrospinal fluid around twenty minutes in humans and rats. Moreover, oxytocin itself suffers from several additional drawbacks: a lack of specificity, an extremely poor oral absorption and distribution, and finally, a lack of patentability. Recently, a first non-peptide full agonist of oxytocin receptor (LIT-001) of low molecular weight has been synthesized with reported beneficial effect for social interactions after peripheral administration. In the present study, we report that a single intraperitoneal administration of LIT-001 in a rat model induces a long-lasting reduction in inflammatory pain-induced hyperalgesia symptoms, paving the way to an original drug development strategy for pain treatment.
Learn More >Chronic pain is a major clinical problem of which the mechanisms are incompletely understood. Here, we describe the concept that PI16, a protein of unknown function mainly produced by fibroblasts, controls neuropathic pain. The spared nerve injury (SNI) model of neuropathic pain increases PI16 protein levels in fibroblasts in dorsal root ganglia (DRG) meninges and in the epi/perineurium of the sciatic nerve. We did not detect PI16 expression in neurons or glia in spinal cord, DRG, and nerve. Mice deficient in PI16 are protected against neuropathic pain. In vitro, PI16 promotes transendothelial leukocyte migration. In vivo, mice show reduced endothelial barrier permeability, lower leukocyte infiltration and reduced activation of the endothelial barrier regulator MLCK, and reduced phosphorylation of its substrate MLC2 in response to SNI. In summary, our findings support a model in which PI16 promotes neuropathic pain by mediating a cross-talk between fibroblasts and the endothelial barrier leading to barrier opening, cellular influx, and increased pain. Its key role in neuropathic pain and its limited cellular and tissue distribution makes PI16 an attractive target for pain management.
Learn More >Pediatric chronic pain has often been examined from a risk perspective, and relatively less is known about the individual and family-level resilience factors that help youth with chronic pain maintain their quality of life. This cross-sectional study: (a) examined the relations among purported youth and parent resilience (youth pain acceptance and pain self-efficacy, parent psychological flexibility) and risk (youth pain intensity, parent protectiveness) factors with youth quality of life, and (b) tested exploratory statistical mechanisms that may explain relations between parent and youth variables.
Learn More >Acupuncture has been shown to be effective for the treatment of chronic musculoskeletal back, neck, and osteoarthritis pain. However, access to acupuncture treatment has been limited in medically underserved and low-income populations.
Learn More >The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent case-control cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci.
Learn More >Emerging immunotherapies with monoclonal antibodies against programmed cell death protein-1 (PD-1) have shown success in treating cancers. However, PD-1 signaling in neurons is largely unknown. We recently reported that dorsal root ganglion (DRG) primary sensory neurons express PD-1 and activation of PD-1 inhibits neuronal excitability and pain. Opioids are mainstay treatments for cancer pain, and morphine produces antinociception via mu opioid receptor (MOR). Here, we report that morphine antinociception and MOR signaling require neuronal PD-1. Morphine-induced antinociception after systemic or intrathecal injection was compromised in mice. Morphine antinociception was also diminished in wild-type mice after intravenous or intrathecal administration of nivolumab, a clinically used anti-PD-1 monoclonal antibody. In mouse models of inflammatory, neuropathic, and cancer pain, spinal morphine antinociception was compromised in mice. MOR and PD-1 are coexpressed in sensory neurons and their axons in mouse and human DRG tissues. Morphine produced antinociception by (i) suppressing calcium currents in DRG neurons, (ii) suppressing excitatory synaptic transmission, and (iii) inducing outward currents in spinal cord neurons; all of these actions were impaired by PD-1 blockade in mice. Loss of PD-1 also enhanced opioid-induced hyperalgesia and tolerance and potentiates opioid-induced microgliosis and long-term potentiation in the spinal cord in mice. Last, intrathecal infusion of nivolumab inhibited intrathecal morphine-induced antinociception in nonhuman primates. Our findings demonstrate that PD-1 regulates opioid receptor signaling in nociceptive neurons, leading to altered opioid-induced antinociception in rodents and nonhuman primates.
Learn More >Complex Regional Pain Syndrome (CRPS) presents as chronic, continuous pain and sensory, autonomic, and motor abnormalities affecting one or more extremities. People with CRPS can also show changes in their perception of and attention to the affected body part and sensory information in the affected side of space. Prism Adaptation (PA) is a behavioural intervention targeted at reducing attention deficits in post-stroke hemispatial neglect. PA also appears to reduce pain and other CRPS symptoms; however, these therapeutic effects have been demonstrated only in small unblinded studies. This paper describes the protocol for an ongoing double-blind, randomized, sham-controlled clinical trial that will evaluate the efficacy of PA treatment for CRPS. The secondary aims of the study are to examine the relationships between neuropsychological changes (such as spatial attention, space and body representation, and motor spatial performance) and clinical manifestations of CRPS, as well as symptom improvement.
Learn More >Itch is a unique sensation that helps organisms scratch away external threats; scratching itself induces an immune response that can contribute to more itchiness. Itch is induced chemically in the peripheral nervous system via a wide array of receptors. Given the superficial localization of itch neuron terminals, cells that dwell close to the skin contribute significantly to itch. Certain mechanical stimuli mediated by recently discovered circuits also contribute to the itch sensation. Ultimately, in the spinal cord, and likely in the brain, circuits that mediate touch, pain, and itch engage in cross modulation. Much of itch perception is still a mystery, but we present in this review the known ligands and receptors associated with itch. We also describe experiments and findings from investigations into the spinal and supraspinal circuitry responsible for the sensation of itch. Expected final online publication date for the , Volume 43 is July 8, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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