Articles: hyperalgesia.
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Delta opioid receptor (DOR) agonists have been identified as a promising novel therapy for headache disorders. DORs are broadly expressed in several peripheral and central regions important for pain processing and mood regulation; and it is unclear which receptors regulate headache associated symptoms. In a model of chronic migraine-associated pain using the human migraine trigger, nitroglycerin, we observed increased expression of DOR in cortex, hippocampus, and striatum; suggesting a role for these forebrain regions in the regulation of migraine. ⋯ In a model reflecting negative affect associated with migraine, SNC80 was only effective in loxP controls and not Dlx-DOR mice. Similarly, SNC80 was ineffective in the cortical spreading depression model of migraine aura in conditional knockout mice. Taken together, these data indicate that forebrain DORs are necessary for the action of DOR agonists in relieving headache-related symptoms and suggest that forebrain regions may play an important role in migraine modulation.
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The present study was performed to determine neuronal loci and individual molecular mechanisms responsible for remifentanil-induced hyperalgesia. The effect of methylnaltrexone (MNX) on remifentanil-induced behavioral hyperalgesia was assessed to distinguish contributions of the peripheral and/or central nervous system to remifentanil-induced hyperalgesia. Phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) in the dorsal root ganglion (DRG) neurons after remifentanil infusion, and the effect of a p38MAPK inhibitor on remifentanil-induced hyperalgesia were analyzed to investigate involvement of p38MAPK in the peripheral mechanisms of remifentanil-induced hyperalgesia. ⋯ Prodynorphin expression increased in the spinal cord, and a BK2 antagonist inhibited hyperalgesia during the late post-infusion period. Remifentanil-induced exacerbation of incisional hyperalgesia was inhibited by MNX and the BK2 antagonist. The present study demonstrated that remifentanil activates peripheral and spinal neurons to promote chronologically distinctive hyperalgesia. p38MAPK phosphorylation in the DRG neuron leads to peripherally-driven hyperalgesia during the early post-infusion period, while spinal dynorphin-bradykinin signaling promotes hyperalgesia during the late post-infusion period.
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It was recently shown that local injection, systemic administration or topical application of the peripherally-restricted mu-opioid receptor (MOR) agonist loperamide (Lo) and the delta-opioid receptor (DOR) agonist oxymorphindole (OMI) synergized to produce highly potent anti-hyperalgesia that was dependent on both MOR and DOR located in the periphery. We assessed peripheral mechanisms by which this Lo/OMI combination produces analgesia in mice expressing the light-sensitive protein channelrhodopsin2 (ChR2) in neurons that express NaV1.8 voltage-gated sodium channels. These mice (NaV1.8-ChR2+) enabled us to selectively target and record electrophysiological activity from these neurons (the majority of which are nociceptive) using blue light stimulation of the hind paw. ⋯ Teased fiber recording of tibial nerve fibers innervating the plantar hind paw revealed that the Lo/OMI combination reduced responses to light stimulation in naïve mice and attenuated spontaneous activity (SA) as well as responses to light and mechanical stimuli in CFA-treated mice. These results show that Lo/OMI reduces activity of C-fiber nociceptors that express NaV1.8 and corroborate recent behavioral studies demonstrating the potent analgesic effects of this drug combination. Because of its peripheral site of action, Lo/OMI might produce effective analgesia without the side effects associated with activation of opioid receptors in the central nervous system.
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Randomized Controlled Trial
Treatment effects on pain catastrophizing and cutaneous allodynia symptoms in women with migraine and overweight/obesity.
Pain catastrophizing and cutaneous allodynia represent two risk factors for greater headache-related disability. Yet, there is limited knowledge of the extent to which these risk factors are modifiable and whether nonpharmacological treatment-related changes are associated with migraine improvements. Using data from the Women's Health and Migraine (WHAM) study, a randomized controlled trial that compared effects of behavioral weight loss (BWL) and migraine education (ME) in women with migraine and overweight/obesity, we tested whether: (a) BWL versus ME produced greater changes in pain catastrophizing and allodynia from baseline across posttreatment and follow-up time points, and (b) whether these improvements were associated with improvements in headache disability. ⋯ Pain catastrophizing and allodynia are not only reduced after nonpharmacologic treatments for migraine, but greater improvements are associated with greater reductions in headache-related disability, independent of migraine severity. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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Acta neurologica Belgica · Oct 2020
Association of dynamic and widespread mechanical sensitivity in cluster headache.
We investigated if dynamic pressure pain sensitivity in the symptomatic area is associated with pressure sensitivity in local and distant pain-free areas in cluster headache (CH). A pressure algometry set consisting of 8 rollers with fixed pressure levels ranging from 500 to 5300 g was used to assess dynamic pressure pain sensitivity in men with episodic CH. Each roller was moved from an anterior-to-posterior direction over the temporalis muscle. ⋯ Further, DPT, but not roller-evoked pain, was moderately associated with PPTs measured at the symptomatic (temporalis: r = 0.665, P < 0.001) and distant pain-free (C5-C6 joint: r = 0.389, P = 0.013; second metacarpal: r = 0.551, P < 0.001; and, tibialis anterior: r = 0.308, P = 0.035) points. Dynamic pressure sensitivity in the trigeminal area was correlated to pressure pain sensitivity at both symptomatic and distant pain-free areas in men with CH supporting the use of roller pressure algometry. Dynamic pressure algometry may be a new tool for assessing the status of sensitization in primary headaches.