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The sensation of pruritus, or itch, is associated with a variety of skin and medical disorders. Itch is transmitted through afferent C-fibers, and sodium channels play a key role in the transmission process. Local anesthetics, which block sodium channels, are used topically to treat itch, but generally have a short duration of action and are not selective for afferent nerves underlying the itch sensation. Accordingly, there is a substantial unmet need for safe, efficacious, long-acting treatments for chronic pruritus, including non-histaminergic itch. We investigated the dose-response, time to onset and duration of action of ASN008 topical gel, which targets small afferent sodium channels, in a murine model of pruritus in which scratching behavior is induced by intradermal injection of chloroquine into the nape of the neck of C57BL/6 mice. Topical application of ASN008 gel resulted in a concentration-dependent reduction of scratching behavior. Onset of action was ≤ 1 hour and duration of scratching inhibition was 15-24 hours. In a further study involving once-daily application for 5 days with chloroquine challenge on day 5, treatment with ASN008 gel again resulted in a concentration-dependent reduction of chloroquine-induced scratching, even when the gel was removed 3 hours after each daily application. In conclusion, topical ASN008 gel produces a dose-dependent reduction of scratching in a mouse model of pruritus, with a rapid onset and long duration of action, and may prove to be an effective, once-daily treatment for a variety of pruritic conditions in humans, including non-histaminergic itch. SIGNIFICANCE STATEMENT: ASN008 gel produces a dose-dependent reduction of scratching in a mouse model of pruritus, with a rapid onset and long duration of action, and may prove to be an effective, once or twice-daily treatment for a variety of pruritic conditions in humans, including non-histaminergic itch. ASN008 topical gel is currently under investigation in Phase 1 clinical studies to evaluate safety, tolerability, pharmacokinetics and preliminary anti-pruritic efficacy in atopic dermatitis patients (ClinicalTrials.gov ID: NCT03798561).
Purine receptors play roles in peripheral and central sensitization and are associated with migraine headache. We investigated the possibility that ATP plays a permissive role in the activation of AMPA receptors thus inducing Glu release from nerve terminals isolated from the rat trigeminal caudal nucleus (TCN).
Ubrogepant, a small-molecule calcitonin gene-related peptide receptor antagonist, was recently approved as an oral medication for the acute treatment of migraine. This study aimed to determine whether ubrogepant shows efficacy in a preclinical model of migraine-like pain and whether repeated oral administration of ubrogepant induces latent sensitization relevant to medication overuse headache in rats.
Migraine, especially migraine with aura (MA), has been linked to increased risk for ischemic cerebrovascular disease. The possible role of elevated serum homocysteine (Hcy, a cause of thrombophilia) in migraine has been demonstrated by several studies.
Preclinical evidence has highlighted the importance of the μ-opioid peptide (MOP) receptor on primary afferents for both the analgesic actions of MOP receptor agonists, as well as the development of tolerance, if not opioid-induced hyperalgesia. There is also growing interest in targeting other opioid peptide receptor subtypes (δ-opioid peptide [DOP], κ-opioid peptide [KOP], and nociceptin/orphanin-FQ opioid peptide [NOP]) on primary afferents, as alternatives to MOP receptors, which may not be associated with as many deleterious side effects. Nevertheless, results from several recent studies of human sensory neurons indicate that although there are many similarities between rodent and human sensory neurons, there may also be important differences. Thus, the purpose of this study was to assess the distribution of opioid receptor subtypes among human sensory neurons. A combination of pharmacology, patch-clamp electrophysiology, Ca imaging, and single-cell semiquantitative polymerase chain reaction was used. Our results suggest that functional MOP-like receptors are present in approximately 50% of human dorsal root ganglion neurons. δ-opioid peptide-like receptors were detected in a subpopulation largely overlapping that with MOP-like receptors. Furthermore, KOP-like and NOP-like receptors are detected in a large proportion (44% and 40%, respectively) of human dorsal root ganglion neurons with KOP receptors also overlapping with MOP receptors at a high rate (83%). Our data confirm that all 4 opioid receptor subtypes are present and functional in human sensory neurons, where the overlap of DOP, KOP, and NOP receptors with MOP receptors suggests that activation of these other opioid receptor subtypes may also have analgesic efficacy.
Glucagon-like peptide-1 receptor has anti-apoptotic, anti-inflammatory, and neuroprotective effects. It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory responses; however, it is not clear whether glucagon-like peptide-1 receptor regulates chronic pain via anti-inflammatory mechanisms. We explored the effects of glucagon-like peptide-1 receptor on nociception, cognition, and neuroinflammation in chronic pain. A rat model of chronic pain was established using left L5 spinal nerve ligation. The glucagon-like peptide-1 receptor agonist exendin-4 was intrathecally injected into rats from 10 to 21 days after spinal nerve ligation. Electrophysiological examinations showed that, after treatment with exendin-4, paw withdrawal frequency of the left limb was significantly reduced, and pain was relieved. In addition, in the Morris water maze test, escape latency increased and the time to reach the platform decreased following exendin-4 treatment. Immunohistochemical staining and western blot assays revealed an increase in the numbers of activated microglia and astrocytes in the dentate gyrus of rat hippocampus, as well as an increase in the expression of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6. All of these effects could be reversed by exendin-4 treatment. These findings suggest that exendin-4 can alleviate pain-induced neuroinflammatory responses and promote the recovery of cognitive function via the glucagon-like peptide-1 receptor pathway. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Renmin Hospital of Wuhan University of China (approval No. WDRM 20171214) on September 22, 2017.
Chronic neck pain is reportedly considered the fourth leading cause of disability. Cervical interlaminar epidural injections are among the commonly administered nonsurgical interventions for managing chronic neck pain, secondary to disc herniation and radiculitis, spinal stenosis, or chronic neck pain of discogenic origin.