Pain
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Pain and hypersensitivity months after peripheral injury reflect abnormal input from peripheral afferents likely in conjunction with central sensitization. We hypothesize that peripheral changes occur in defined sensory afferents and resolve as behavioral response to injury resolves. Male Sprague-Dawley rats underwent sham or partial L5 spinal nerve ligation, and paw withdrawal threshold (PWT) was sequentially measured during recovery. ⋯ After resolution of behavioral changes, several electrical abnormalities persisted in both neuronal subtypes. These data extend previous findings that mechanically sensitive nociceptors are sensitized, whereas tactile, largely Aβ afferents are desensitized after nerve injury by showing that the time course of resolution of these changes mirrors that of behavioral hypersensitivity in a surgical injury including neural damage. These data support a role of abnormal peripheral input, from both nociceptor and tactile afferents, during recovery from peripheral injury and underscore the potential importance of both classes of afferents as potential targets for pain treatment.
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Migraine headache pathophysiology involves trigeminovascular system activation, calcitonin gene-related peptide (CGRP) release, and dysfunctional nociceptive transmission. Triptans are 5-HT1B/1D/(1F) receptor agonists that prejunctionally inhibit trigeminal CGRP release, but their vasoconstrictor properties limit their use in migraine patients with cardiovascular disease. By contrast, lasmiditan is a novel antimigraine and selective 5-HT1F receptor agonist devoid of vasoconstrictor properties. ⋯ In vivo, intravenous (i.v.) lasmiditan or higher doses of sumatriptan significantly attenuated the vasodilatory responses to endogenous CGRP release, but not exogenous CGRP effects. These data suggest that lasmiditan prejunctionally inhibits CGRP release in peripheral and central trigeminal nerve terminals. Because lasmiditan is a lipophilic drug that crosses the blood-brain barrier, additional central sites of action remain to be determined.
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Alleviating chronic pain is challenging, due to lack of drugs that effectively inhibit nociceptors without off-target effects on motor or central neurons. Dorsal root ganglia (DRG) contain nociceptive and non-nociceptive neurons. Drug screening on cultured DRG neurons, rather than cell lines, allows for the identification of drugs most potent on nociceptors with no effects on non-nociceptors (as a proxy for unwanted side effects on central nervous system and motor neurons). ⋯ We confirmed the link between the oscillatory profile and nociceptors, and the slow-decay profile and non-nociceptors using 3 transgenic mouse lines of known pain phenotypes. We used the assay to show that blockers for Nav1.7 and Nav1.8 channels, which are validated targets for analgesics, affect non-nociceptors at concentrations needed to effectively inhibit nociceptors. However, a combination of low doses of both blockers had an additive effect on nociceptors without a significant effect on non-nociceptors, indicating that the assay can also be used to screen for combinations of existing or novel drugs for the greatest selective inhibition of nociceptors.