Pain perception is initiated upon activation of nociceptors of the dorsal root ganglia (DRG) and trigeminal ganglia. We identify G-protein-coupled receptors (GPCRs) expressed in CGRP[+] mouse and human DRG neurons and find that agonists of several identified Gi/o-coupled and orphan GPCRs attenuate neuronal excitability. Experiments focusing on the Gi/o-coupled serotonin receptor Htr1b, which is expressed in mouse and human CGRP[+] DRG neurons, reveal that Htr1b/1d agonists, the triptans sumatriptan and zolmitriptan, attenuate CGRP[+] neuron excitability in vitro and exhibit analgesia across several pain models, including neuropathic pain. Conditional genetic deletion experiments show that triptan-induced analgesia is mediated by Htr1b expressed in A-fiber mechanonociceptors. Also, triptan-associated adverse effects are partially mediated by Htr1b-independent targets. Further testing identifies the GPCR Gpr19 as an additional promising target for treating pain. These findings establish a preclinical screening platform for identifying analgesic candidates and reveal nociceptor GPCRs that may be targeted to treat pain.

Terminal sterilisation is a critical process for pharmaceutical products intended for parenteral or invasive administration, yet conventional sterilisation approaches can compromise thermolabile or chemically sensitive drug substances. In this study, the compatibility of crystalline and amorphous solid forms of five drug substances (betamethasone dipropionate (BMD), estradiol (E2), itraconazole (ITZ), vismodegib (VDG), and zolmitriptan (ZMT)) with sterilising gamma irradiation and ethylene oxide (EtO) cycles was evaluated in terms of chemical and physical stability. Physical stability was assessed by visual inspection of crystalline powders and amorphous solids pre- and post-sterilisation and by differential scanning calorimetry (DSC) to characterise the melting behaviour of crystalline drugs, and glass transition and recrystallisation events in amorphous forms. Chemical stability was examined using reverse phase-high-performance liquid chromatography (RP-HPLC), liquid chromatography-mass spectrometry (LC-MS), and proton nuclear magnetic resonance spectroscopy (¹H-NMR). Gamma irradiation and EtO preserved the chemical integrity of BMD, E2, ITZ, and VDG. A reversible colour change observed for ITZ was attributed to radical formation as confirmed by gentle heating, HPLC and LC-MS. E2 demonstrated alterations in crystallinity and thermal behaviour after sterilisation, despite maintaining chemical integrity. ZMT exhibited pronounced sensitivity to sterilisation: gamma irradiation induced physical softening and oxidative degradation, particularly in the amorphous form, while EtO sterilisation induced ZMT hydroxyethylation, as confirmed by LC-MS identification of multiple alkylated derivatives. Overall, sterilisation compatibility was governed primarily by molecular structure rather than the drug solid-state. These findings provide an insight for selecting sterilisation strategies and facilitate the translation of crystalline and amorphous pharmaceutical solids toward clinical application.

Migraines represent one of the most prevalent and debilitating neurological disorders. In terms of quality-of-life impairment and the degree of disability incurred, severe migraine attacks align with the World Health Organization (WHO) level 7 disability, comparable to conditions such as tetraparesis, psychosis, and dementia. The severity of migraine attacks is influenced not only by the intensity of the headache but also by the severity of accompanying non-pain symptoms, which include nausea, vomiting, photophobia, phonophobia, dizziness, and cognitive impairment, as well as the frequency of recurrence. The presence of nausea or vomiting during a migraine attack is indicative of migraine-associated gastroparesis, which adversely affects the bioavailability and efficacy of oral medications. Consequently, these factors contribute to the limited effectiveness of standard tablet formulations in aborting migraine attacks. This article explores contemporary approaches to treating migraine attacks and new criteria for assessing therapeutic efficacy. Particular emphasis is placed on the effectiveness of orally disintegrating tablets (ODT) of rizatriptan compared with sumatriptan and zolmitriptan. Optimal management of a migraine attack necessitates an individualized approach that considers the severity of the condition, the spectrum of clinical manifestations, and the selection of an appropriate pharmaceutical formulation. Strong evidence supports the assertion that rizatriptan 10 mg ODT (Kaporiza) is one of the most rapid, effective, and convenient options for the abortive treatment of migraine attacks in the majority of patients.

Migraine is a chronic neurological disorder that necessitates swift and efficient treatment. Zolmitriptan (ZMT) is a first-line agent with low oral bioavailability and a slow onset of action. Intranasal delivery represents one of the noninvasive routes, directly targeting the nose-to-brain pathway. Therefore, a nano-liposomal system for the co-encapsulation of Zolmitriptan and Ginkgolide B (GB) was developed for efficient intranasal synergistic migraine therapy. The preparation of co-loaded liposomes was performed by thin-film hydration and then optimized by means of DoE. The nanoparticles of the optimal formulation had a mean diameter of 73.13 ± 10.45 nm, high entrapment efficiencies for both ZMT and GB (94.88 ± 2.0% and 95.41 ± 1.3%, respectively) and a biphasic pattern of drug release: a fast burst release of ZMT during the first 2 hours (95.69 ± 4.58%), followed by sustained release of GB within 8 hours (cumulative amount of 98.37 ± 2.87%). The ex vivo permeation study further demonstrated an increased transport across the olfactory mucosa compared to the control treatments. The formulation was well cytocompatible against the nasal cell line (>80% cell viability) and stable upon storage at refrigerated conditions. In this way, it is emphasized that this new dual-drug co-loaded liposomal system may be of great promise in providing improved migraine management through direct brain delivery, but needs in vivo experimentation.

Pain perception is initiated upon activation of nociceptors of the dorsal root ganglia (DRG) and trigeminal ganglia. We identified G protein-coupled receptors (GPCRs) expressed in CGRP [+] mouse and human DRG neurons and found that agonists of several identified G i/o -coupled and orphan GPCRs attenuated neuronal excitability. Experiments focusing on the G i/o -coupled serotonin receptor Htr1b, which is expressed in mouse and human CGRP [+] DRG neurons, revealed that Htr1b/1d agonists, the triptans sumatriptan and zolmitriptan, attenuated CGRP [+] neuron excitability in vitro and exhibited analgesia across several pain models, including neuropathic pain. Conditional genetic deletion experiments showed that triptan-induced analgesia is mediated by Htr1b expressed in A-fiber mechanonociceptors. Also, triptan-associated adverse effects are partially mediated by Htr1b-independent targets. Further testing identified the GPCR Gpr19 as an additional promising target for treating pain. These findings establish a preclinical screening platform for identifying novel analgesics and reveal nociceptor GPCRs that may be targeted to treat pain.

Congenital demyelinating peripheral neuropathy causes severe sensorimotor defects, affecting patient mobility. To identify therapeutic compounds for peripheral hypomyelinating neuropathy, we performed an unbiased screening of annotated compound library by in vitro myelination culture model using Trembler (Tr-Ncnp) -derived dorsal root ganglia explants. Among the compounds identified in the screening, we confirmed that zolmitriptan, a 5-hydroxytryptamine 1B/1D receptor agonist, promotes myelination in culture. Zolmitriptan up-regulated myelin-related genes in primary Schwann cells and increased proliferating Schwann cells along axons in DRG explant cultures of Tr-Ncnp mice. Furthermore, we observed that chronic administration of zolmitriptan ameliorates sensorimotor dysfunction in Tr-Ncnp mice. Collectively, these results suggest that 5-HT1B/1D receptor agonists may increase Schwann cells participating in myelination, and consequently ameliorate myelination impairment in peripheral neuropathy.

Sensory transmission in the monosynaptic stretch reflex (MSR) from proprioceptive Ia afferents to motoneurons is markedly inhibited by serotonin, providing a mechanism by which the brain gates spinal cord function. However, the main serotonin receptor subtype that modulates the MSR is the 5-HT1D receptor that is expressed almost exclusively on nociceptive C-fibres, suggesting an unexpected gating of proprioceptive transmission by regulation of nociceptive pathways. We demonstrate here that activation of C-fibres (electrically or pharmacologically by TRPM8 agonists) increases action potential propagation in proprioceptive Ia afferents by producing a very long-lasting tonic depolarization in Ia afferents (tonic primary afferent depolarization, tonic PAD). This tonic PAD is produced indirectly by C-fibres augmenting axoaxonic GABAergic input onto Ia afferents (bicuculline sensitive), which activates nodal GABAA receptors that aid sodium spike initiation. In contrast, activation of 5-HT1D receptors with the anti-migraine drug zolmitriptan inhibits C-fibre activity, which in turn reduces the GABAA receptor-mediated tonic PAD on Ia afferents, and reduces spike propagation to motoneurons. Overall, these findings demonstrate a mechanism by which brainstem derived serotonin not only inhibits ongoing nociceptive C-fibres activity, but also indirectly inhibits GABAergic neurons and sensory transmission in large proprioceptive sensory afferents, leading to reduced motoneuron activity. Furthermore, these findings suggest that spontaneous nociceptive C-fibres activity may provide a general increase in proprioception, opposite to the classical gating of nociceptive pathways by low threshold afferents, and impacting the clinical use of zolmitriptan.

BackgroundHigh-quality research studies on therapeutic approaches for migraine management in pediatrics are scarce. Therefore, we conducted a systematic review of current clinical practice guidelines for the diagnosis and management of migraine in children and adolescents to identify areas of consensus and disagreement, as well as critical gaps, paving the way for future updates and improvements.MethodsWe searched PubMed, WOS, and SCOPUS for guidelines published in the English language in the last 10 years focused on the diagnosis and management of migraine in children and adolescents.ResultsFollowing a systematic search, eight eligible guidelines were identified. These guidelines were authored by the American Academy of Neurology (AAN), the European Headache Federation/European Academy of Neurology (EHF/EAN), the International Headache Society (IHS), National Institute for Health and Care Excellence (NICE), the Danish Headache Society, and the German Migraine and Headache Society and the German Society of Neurology. There was a broad consensus on considering the International Classification of Headache Disorders-3rd edition as the diagnostic reference. As regards management, paracetamol and ibuprofen were considered first line in the acute management of migraine, with sumatriptan and zolmitriptan nasal sprays rated as second line. Injectable medications for acute management were overlooked in most guidelines. On the other hand, targeted age groups, dosing, and preventive treatment choices showed areas of variability. Various non-pharmacological measures gained attention in all guidelines. Notably, CGRP antagonists and non-invasive neuromodulation techniques were identified as major gaps.ConclusionThe current systematic review highlights areas of agreement and disagreement between existing guidelines on the management of childhood and adolescent migraine and emphasizes the current gaps and opportunities, thus offering a solid foundation for future studies and guidelines.

Serotonin 1b (5-HT 1b) receptors play an important role in preclinical cocaine effects. Zolmitriptan, a commercially available 5-HT 1b / 1d agonist migraine medication, selectively attenuates the reinforcing and other abuse-related effects of cocaine. This project sought to advance these promising preclinical findings into humans, thereby demonstrating that the 5-HT 1b/1d system plays a key role in the abuse-related effects of cocaine in people with cocaine use disorder (CUD). Twelve nontreatment-seeking individuals (four female human subjects) with CUD participated in this within-subject human laboratory study. Participants were maintained on 0, 2.5, 5, and 10 mg oral zolmitriptan/day in random order. After at least 3 days of maintenance on each target dose, participants completed experimental sessions in which the reinforcing, subjective, physiological, and cognitive-behavioral effects of 0, 10, and 30 mg/70 kg of intravenous cocaine were determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g. increased ratings of 'stimulated' and heart rate). Zolmitriptan produced limited changes in oral temperature after 10 mg/70 kg cocaine. Cocaine administration improved working memory impairments observed under the 5 mg zolmitriptan condition. Zolmitriptan did not alter any other effects of cocaine. Data indicate that activating the 5-HT 1b/1d systems through zolmitriptan maintenance produces limited changes in the pharmacodynamic effects of cocaine in humans, contrasting preclinical findings, suggesting this may not be a promising pharmacotherapeutic strategy for CUD. Failing to translate from preclinical to clinical models could be because of methodological or species differences, suggesting the field needs to better address this translational gap.

Background: It is critical for rescue medications to have rapid absorption and onset of action. Although intranasal formulations of rescue medications have advantages over other forms of administration, the impact of nasal congestion on drug absorption has been questioned. Objective: We aimed to determine if nasal congestion impacts the absorption and efficacy of intranasal rescue medications. Methods: A rescue medication is used as needed for the immediate treatment of an episodic medical event that requires urgent intervention. Systematic searches for 15 pre-identified intranasal rescue medications were conducted in PubMED/MEDLINE up to July 2, 2024. Eligible studies were controlled human studies that compared the absorption or efficacy of an identical dose of intranasal rescue medication administered with and without the presence of nasal congestion that was induced by allergen challenge or that was associated with a medical condition (e.g., allergic rhinitis). Results: The searches identified 160 articles; six studies, all open-label, were eligible for final inclusion. Two intranasal epinephrine studies showed increased maximum plasma concentrations after allergen-induced congestion; one of these epinephrine studies also showed a faster time to maximum plasma concentration. Three additional studies that evaluated epinephrine, glucagon, and fentanyl found no effect of congestion on absorption. In the sixth study, congestion had no effect on zolmitriptan efficacy. Conclusion: Available evidence indicates no negative impact of nasal congestion on the absorption of intranasal rescue medications. Congestion may actually increase absorption of some intranasal epinephrine formulations. The impact of congestion on intranasal medication absorption is likely dependent on each drug's properties, mode of action, and formulation.