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Pain measures traditionally used in rodents record mere reflexes evoked by sensory stimuli; the results thus may not fully reflect the human pain phenotype. Alterations in physical and emotional functioning, pain-depressed behaviors and facial pain expressions were recently proposed as additional pain outcomes to provide a more accurate measure of clinical pain in rodents, and hence to potentially enhance analgesic drug development. We aimed to review how preclinical pain assessment has evolved since the development of the tail flick test in 1941, with a particular focus on a critical analysis of some nonstandard pain outcomes, and a consideration of how sex differences may affect the performance of these pain surrogates. We tracked original research articles in Medline for the following periods: 1973-1977, 1983-1987, 1993-1997, 2003-2007, and 2014-2018. We identified 606 research articles about alternative surrogate pain measures, 473 of which were published between 2014 and 2018. This indicates that preclinical pain assessment is moving toward the use of these measures, which may soon become standard procedures in preclinical pain laboratories.
Learn More >Here we investigated effects of intramuscular (i.m.) heating-needle stimulation on persistent muscle nociception evoked by i.m. injection of different doses (50-200 µl) of complete Freund's adjuvant (CFA) in rats. Paw withdrawal reflexes evoked by noxious mechanical and heat stimulation as well as hind limb swelling were determined prior to and two weeks after the CFA injection. The unilateral injection of CFA induced a dose-related and long-lasting (5-14d), bilateral secondary mechanical hyperalgesia and heat hypoalgesia associated with long-term limb swelling. A period of 30-45 min 43 °C heating-needle stimulation significantly enhanced the i.m. CFA-induced bilateral heat hypoalgesia and alleviated hind limb swelling. In contrast, 30-45min 46 °C heating-needle stimulation markedly enhanced both mechanical hyperalgesia and heat hypoalgesia, but failed to influence the CFA-induced hind limb swelling. Microinjection of P2X3 receptor antagonist A-317491 (0.5-4.5 nmol/0.5µl) into the thalamic ventromedial (VM) nucleus dose-dependently inhibited the 43 °C and 46 °C heating-needle stimulation-induced heat hypoalgesia, whereas the 46 °C heating-needle stimulation-induced mechanical hyperalgesia was significantly prevented by microinjection of A-317491 into the thalamic mediodorsal (MD) nucleus. In contrast, the hind limb swelling was not affected by the microinjection of A-317491 into the thalamic VM or MD nucleus. The present study indicates that in the CFA-induced persistent muscle nociception condition, 43 °C heating-needle stimulation selectively increases descending inhibition, which effect is modulated by the thalamic VM nucleus. In addition to the antinociceptive role of P2X3 receptors in the thalamic VM nucleus, P2X3 receptors within the thalamic MD nucleus participate in the descending facilitation evoked by i.m. 46 °C heating-needle stimulation.
Learn More >SHANK3 is one of the scaffolding proteins in the postsynaptic density (PSD). Pain perception and underlying mechanisms were investigated in Shank3 exon 21 deficient (Shank3) mice. Sixty-six mice were attributed according to their genotype to three groups: (1) wild-type (WT), (2) heterozygous Shank3, and (3) homozygous Shank3. Complete Freund's adjuvant (CFA) was used to induce inflammatory pain, and thermal hyperalgesia was determined. CFA treatment reduced the thermal threshold in the WT group; groups expressing mutations of Shank3 ( and ) had higher thresholds after CFA administration compared to the WT group. Mice with Shank3 mutations ( or ) had a lower expression of GluN2A and IPR proteins and a higher expression of mGluR5 protein in the PSD compared to WT mice without changes in GluN1, GluN2B, and Homer expression. The crosslinking of Homer-IPR, but not Homer-mGluR5, was decreased in the total lysate. Deficit of Shank3 exon 21 may lead to impaired perception of thermal pain in mice under inflammatory conditions. This impairment may result from protein dysregulation in the PSD like downregulation of the GluN2A subunit, which may reduce NMDAR-mediated currents, and/or decreased crosslinking between Homer and IPR, which may reduce the release of Ca from intracellular stores.
Learn More >Psychological stress and ensuing modulation of the immune and nervous systems can have a significant impact on itch. Stress can exacerbate itch and vice versa, resulting in a vicious cycle that can greatly impair a patient's quality of life. This review summarizes the association between stress and itch, elucidates the mechanism by which these two phenomena influence one another, and explores treatment modalities that aim to reduce stress-induced itch.
Learn More >Triptans are the most commonly used acute treatment for migraine. This study evaluated real-world treatment patterns following an initial triptan prescription to understand refill rates and use of non-triptan medications for the acute treatment of migraine.
Learn More >We have previously shown that endogenous adenosine 5'-triphosphate (ATP), via P2X3 and P2X2/3 receptors, plays an essential role in carrageenan-induced articular hyperalgesia model in rats' knee joint. In the present study, we used the rat knee joint incapacitation test, Enzyme-Linked Immunosorbent Assay (ELISA), and myeloperoxidase enzyme activity assay, to test the hypothesis that the activation of P2X3 and P2X2/3 receptors by their agonist induces articular hyperalgesia mediated by the inflammatory mediators bradykinin, prostaglandin, sympathomimetic amines, pro-inflammatory cytokines and by neutrophil migration. We also tested the hypothesis that the activation of P2X3 and P2X2/3 receptors contributes to the articular hyperalgesia induced by the inflammatory mediators belonging to carrageenan inflammatory cascade. The non-selective P2X3 and P2X2/3 receptors agonist αβ-meATP induced a dose-dependent articular hyperalgesia, which was significantly reduced by the selective antagonists for P2X3 and P2X2/3 receptors (A-317491), bradykinin B- (DALBK) or B-receptors (bradyzide), β-(atenolol) or β-adrenoceptors (ICI-118,551), by the pre-treatment with cyclooxygenase inhibitor (indomethacin) or with the nonspecific selectin inhibitor (Fucoidan). αβ-meATP induced the release of pro-inflammatory cytokines TNFα, IL-1β, IL-6, and CINC-1, as well as the neutrophil migration. Moreover, the co-administration of A-317491 significantly reduced the articular hyperalgesia induced by bradykinin, prostaglandin E (PGE), and dopamine. These findings suggest that peripheral P2X3 and P2X2/3 receptors activation induces articular hyperalgesia by an indirect sensitization of the primary afferent nociceptor of rats' knee joint through the release of inflammatory mediators. Further, they also indicate that the activation of these purinergic receptors by endogenous ATP mediates the bradykinin-, PGE-, and dopamine-induced articular hyperalgesia.
Learn More >Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) may play an important role in primary headaches. Preclinical evidence suggests that PACAP38 modulates trigeminal nociceptive activity mainly through PAC1 receptors while clinical studies report that plasma concentrations of PACAP38 are elevated in spontaneous attacks of cluster headache and migraine and normalize after treatment with sumatriptan. Intravenous infusion of PACAP38 induces migraine-like attacks in migraineurs and cluster-like attacks in cluster headache patients. A rodent-specific PAC1 receptor antibody Ab181 was developed and its effect on nociceptive neuronal activity in the trigeminocervical complex was investigated in vivo in an electrophysiological model relevant to primary headaches. Ab181 is potent and selective at the rat PAC1 receptor and provides near maximum target coverage at 10 mg/kg for more than 48 hours. Without affecting spontaneous neuronal activity, Ab181 effectively inhibits stimulus-evoked activity in the trigeminocervical complex. Immunohistochemical analysis revealed its binding in the trigeminal ganglion and sphenopalatine ganglion but not within the CNS suggesting a peripheral site of action. The pharmacological approach using a specific PAC1 receptor antibody could provide a novel mechanism with a potential clinical efficacy in the treatment of primary headaches.
Learn More >Experimental and clinical data strongly support vagus nerve stimulation (VNS) as a novel treatment in migraine. VNS acutely suppresses cortical spreading depression (CSD) susceptibility, an experimental model that has been used to screen for migraine therapies. However, mechanisms underlying VNS efficacy on CSD are unknown. Here, we interrogated the central and peripheral mechanisms using VNS delivered either invasively (iVNS) or non-invasively (nVNS) in male Sprague-dawley rats. CSD susceptibility was evaluated 40 min after the stimulation. iVNS elevated the electrical CSD threshold more than two-fold and decreased KCl-induced CSD frequency by 22% when delivered to intact vagus nerve. Distal vagotomy did not alter iVNS efficacy (2-fold higher threshold and 19% lower frequency in iVNS vs. sham). In contrast, proximal vagotomy completely abolished iVNS effect on CSD. Pharmacological blockade of nucleus tractus solitarius (NTS), the main relay for vagal afferents, by lidocaine or glutamate receptor antagonist CNQX also prevented CSD suppression by nVNS. Supporting a role for both norepinephrine and serotonin, CSD suppression by nVNS was inhibited by more than 50% after abrogating norepinephrinergic or serotonergic neurotransmission alone using specific neurotoxins; abrogating both completely blocked the nVNS effect. Our results suggest that VNS inhibits CSD through central afferents relaying in NTS and projecting to subcortical neuromodulatory centers providing serotonergic and norepinephrinergic innervation to the cortex.
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