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Triptans are 5-HT receptor agonists (that also display 5-HT receptor affinity) with antimigraine action, contraindicated in patients with coronary artery disease due to their vasoconstrictor properties. Conversely, lasmiditan was developed as an antimigraine 5-HT receptor agonist. To assess the selectivity and cardiovascular effects of lasmiditan, we investigated the binding, functional activity and in vitro/in vivo vascular effects of lasmiditan, and compared it to sumatriptan.
Learn More >Previous studies have shown that α7 nicotinic acetylcholine receptor (nAChR) has a critical role in the regulation of pain sensitivity and neuroinflammation. However, pharmacological effects of α7 nAChR activation in the hippocampus on neuroinflammatory mechanisms associated with allodynia and hyperalgesia remain unknown. We have determined the effects of 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), an α7 nAChR positive allosteric modulator, on lipopolysaccharide (LPS)-induced allodynia and hyperalgesia in mice. We also evaluated the effects of TQS on immunoreactivity of microglial marker ionized-calcium binding adaptor molecule 1 (Iba-1), phospho-nuclear factor-κB (p-NF-κB p), tumor necrosis factor-alpha (TNF-α), and norepinephrine (NE) level.
Learn More >CGRP plays a major role in the pathophysiology of migraine. Concomitant, CGRP plays a role in endogenous neurovascular protection from severe vasoconstriction associated with e.g. cerebral or cardiac ischemia. The CGRP antagonistic antibodies Fremanezumab (TEVA Pharmaceuticals) and Erenumab (Novartis/Amgen) have successfully been developed for the prevention of frequent migraine attacks. Whereas these antibodies might challenge endogenous neurovasular protection during severe cerebral or coronary vasoconstriction, potential future therapeutic CGRP agonists might induce migraine-like headaches in migraineurs. In the current study segments of cerebral artery have been used to obtain mechanistic insight of the CGRP-neutralizing anti-body Fremanezumab in neurovascular regulation in vitro. The basilar artery was selected due to its relevance in subarachnoid hemorrhage (SAH). Erenumab is known to block the human CGRP receptor and Fremanezumab to neutralize both human and rat CGRP. Results confirmed that Erenumab does not block the rat CGRP receptor and that Fremanezumab inhibits the vasodilatory effect induced by both human CGRP, rat CGRP and the metabolically stable CGRP analog, SAX in rat basilar artery. Fremanezumab also inhibits the vasodilatory effect of capsaicin in constricted segments of basilar artery. Capsaicin is used as a pharmacological tool to induce secretion of endogenous perivascular CGRP and our studies confirm that the antibody reach the perivascular sensory synaptic cleft and blocks the vasodilatory response of released CGRP in the present in vitro model. Thus, CGRP neutralization might have the mechanistic potential to block vasoprotective responses to severe vasoconstriction provided they reach the site of action and Fremanezumab is an important tool for future investigations of the impact of CGRP physiology.
Learn More >Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine. This trial evaluated the safety and tolerability of ubrogepant, focusing on hepatic safety, when administered intermittently with high-frequency dosing to healthy participants.
Learn More >Fibromyalgia-associated chronic pain occurring without organic causes exerts negative effects on patients' quality of life, thereby necessitating the development of superior drugs. Since non-organic pain in patients with fibromyalgia occurs without external stimuli, an endpoint measure that reflects patients' spontaneous pain should be implemented in preclinical research. The present study is the first to apply the rat grimace scale (RGS), a facial expression-dependent measure developed for quantifying spontaneous pain, to the rat with reserpine-induced myalgia, an animal model of fibromyalgia exhibiting non-organic pain. Animals were videotaped and still images of facial expressions were captured and scored in a blind fashion. The reserpine-induced myalgia rats exhibited a significant increase in the RGS score, which was sustained for 2 weeks or more after the induction of fibromyalgia-like state by reserpine injection. The period of RGS score elevation was similar to that of reduced paw withdrawal threshold (PWT) measured using the von Frey filament test, a conventional measure of evoked pain. The elevated RGS score and the decreased PWT were relieved by gabapentin (an αδ subunit ligand) and duloxetine (a serotonin and noradrenaline reuptake inhibitor), but not by diclofenac (a nonsteroidal anti-inflammatory drug), buprenorphine (a mu-opioid receptor agonist), or diazepam (a benzodiazepine). The present study suggests that facial expressions in reserpine-induced myalgia rats simulate non-organic pain occurring spontaneously in patients with fibromyalgia. This finding achieves a coordination of pain measures between the animal model and patients with fibromyalgia and would improve the translation of analgesic efficacies between them.
Learn More >Chronic itch is one of the disturbing symptoms of inflammatory skin diseases. Kappa opioid receptor agonists are effective in suppressing scratching in mice against different pruritogens. Nalbuphine, a nonscheduled kappa opioid receptor agonist and mu opioid receptor antagonist, has been in clinical use for post-operative pain management since the 1980s and recently has been in clinical trials for chronic itch of prurigo nodularis (https://www.trevitherapeutics.com/nalbuphine). We studied whether nalbuphine is effective against chronic scratching induced by rostral neck application of 1-fluoro-2,4-dinitrobenzene (DNFB), an accepted mouse model of contact dermatitis to study pruritoceptive itch. Mice were treated once a week with either saline or nalbuphine 20 min before the third, fifth, seventh, and ninth sensitizations with DNFB and the number of scratching bouts was counted for 30 min. Skin samples from the neck of mice at week 4 were used to measure protein levels and mRNA expressions of chemokines and cytokines. Different sets of mice were used to study sedation and anhedonic-like behavior of nalbuphine. We found that: nalbuphine (a) antagonized scratching in a dose- and time-dependent manner without affecting locomotion, b) decreased IL-31, and increased anti-inflammatory IL-10, and c) induced more elevations in the levels of CCL2, CCL3, CCL12, CXCL1, CXCL2, CXCL9, CXCL10, IL-1β, IL-16, TIMP-1, M-CSF, TREM-1 and M1-type macrophages compared to saline. Increases in chemokines and cytokines and M1 macrophages by nalbuphine suggest an inflammatory phase of healing in damaged skin due to scratching. Our data indicate that nalbuphine is an effective antipruritic in murine model of pruritoceptive itch.
Learn More >Aprepitant is a neurokinin 1 receptor (NK1R) antagonist used for its antipruritic properties in dermatoses and systemic diseases. The mode of action is still unclear. A peripheral effect is assumed as aprepitant shows efficacy in inflammatory skin diseases including prurigo nodularis (PN).
Learn More >Efficacy and safety of erenumab have been evaluated in a comprehensive clinical development program resulting in approval for migraine prevention in over 40 countries to date.
Learn More >: Chronic neuropathic pain (NP) is an incapacitating illness caused by alesion of the somatosensory nervous system and is associated with several disease or syndromes. Since current treatment options lack adequate efficacy in the majority of patients, ketamine is often administered to treat refractory NP.: This review gives an overview of new ketamine pharmacokinetic data including data on intranasal and inhaled ketamine. The outcome of seven systematic reviews and meta-analyses, published since 2012, on ketamine efficacy in NP is discussed. The reader will additionally get an understanding of ketamine's complex metabolism with emphasis on the metabolite hydroxynorketamine.: Proof of sustained, large effects of ketamine in the treatment of NP from randomized controlled clinical trials is lacking, although we cannot exclude selective ketamine efficacy in patients with central sensitization, opioid-induced hyperalgesia or opioid tolerance. Interestingly, data from observational trials and case series do suggest efficacy of ketamine in producing effective pain relief in NP with positive patient-related outcome measures. Additional randomized trials in often ill-defined groups of chronic pain patients are not useful and we suggest to conduct future studies in NP patients with central sensitization and/or with opioid refractory severe NP.
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