Abimael González-Hernández

The introduction of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway has revolutionized migraine treatment. In this regard, galcanezumab, a humanized immunoglobulin G4 (IgG4) that binds the CGRP molecule, has rapid onset of action, monthly dosing, and favorable pharmacokinetics. This review, which draws upon electronic databases such as PubMed, Web of Science, FDA, and EMA, provides a comprehensive summary of galcanezumab for migraine prophylaxis. It covers the drug's mechanism of action, its clinical efficacy in episodic migraine, and its potential benefits in episodic cluster headache and medication-overuse headache. It also provides an overall safety profile based on clinical trials and real-world studies. Galcanezumab is a cornerstone preventive therapy with consistent efficacy, favorable tolerability, and convenient dosing. Key unmet needs include identifying biomarkers to predict responders, addressing access and cost barriers, optimizing evaluation windows for late-responders, and expanding the evidence base for special populations (pediatrics, pregnancy, and vascular comorbidities). Future studies should refine patient selection and explore complementary targets for non-responders.

The trigeminal system plays a key role in headaches pathophysiology. In this regard, nociceptive experiments in male rodents have shown that at the trigemi

The ophthalmic branch (V1) of the trigeminal nerve innervating the meningeal and periorbital structures is implicated in the pathophysiology of headaches (e.g. migraine). In this regard, a recent report suggested the existence of bifurcated trigeminal ganglion (TG) cells concurrently projecting to the periphery via the V1 and V2 branches. To reinforce these findings, immunofluorescence experiments were designed to identify TG cells that simultaneously projected to the peripheral region through the V1 and V2 branches. Moreover, since the hypothalamic oxytocinergic system, through oxytocin receptor (OTR) activation, seems to block peripheral trigeminal nociception, a correlation between OTRs and CGRPergic fibres in the meningeal vasculature was explored. In male Wistar rats, retrograde neural tracers injected into the V1 meningeal (True-blue, TB) and V2 infraorbital nerves (IoN; Fluoro-Gold, FG) showed that some TG cells were concomitantly labelled with FG and TB. Furthermore, immunofluorescence assays showed that some TG cells were triple-labelled with CGRP/FG/TB and OTR/FG/TB. In addition, at the meningeal level, OTR seems to be expressed perivascularly and in CGRPergic fibres. To the best of our knowledge, these data support the contention that some TG cells send bifurcated neuronal projections through the V1 and V2 branches. Furthermore, these data reinforce previous suggestions regarding the relevance of OTR in the trigeminovascular system.

Vasoinhibin is a potent antiangiogenic protein that blocks the activation of endothelial nitric oxide synthase (eNOS) in response to vascular endothelial growth factor, bradykinin, and acetylcholine (ACh). In this regard, VIAN‐c4551, a new synthetic vasoinhibin analog, has therapeutic potential for targeting angiogenesis in oncology and ophthalmology. Given that cardiovascular actions are common complications of antiangiogenic drugs and eNOS inhibitors, this multidisciplinary study investigated the cardiovascular safety of VIAN‐c4551. Administered acutely, VIAN‐c4551 inhibited ACh‐induced eNOS phosphorylation/activation in cultured endothelial cells and in lung tissue treated in vivo, as well as the ACh‐induced relaxation of rat aortic segments. However, daily intravenous (i.v.) injections of VIAN‐c4551 (1 or 3 mg kg ⁻¹ ) for 5 days failed to significantly modify the vasodepressor responses to ACh and the baseline values of blood pressure in anesthetized rats (intact, vagotomized, or pithed). Furthermore, daily i.v. injections of 1 mg kg ⁻¹ VIAN‐c4551 (for 5 days) did not alter: (i) blood pressure or heart rate values in awake rats; (ii) cardiac autonomic and histological outcomes in anesthetized animals; or (iii) inflammatory (tumor necrosis factor‐α [TNF‐α] and interleukin‐6 [IL‐6]) and apoptotic (caspase‐3) markers. Although VIAN‐c4551 inhibited ACh‐induced eNOS activation in vitro and in vivo and vasorelaxation in ex vivo assays, in vivo experiments consistently showed no significant cardiovascular effects produced by this synthetic peptide. Thus, VIAN‐c4551 appears to be cardiovascularly safe for targeting angiogenesis‐related diseases.

Background The trigeminal system plays a key role in headaches pathophysiology. In this regard, nociceptive experiments in male rodents have shown that at the trigeminal level, clonidine induces antinociception through α _2A - but not α _2B/2C -adrenoceptors. Interestingly, although behavioural experiments suggest that males are more sensitive to clonidine-induced antinociception than female rats (an effect linked to hormonal factors), little is known about how neuronal nociceptive processing is affected in females (including the role of the α _2A/2B/2C -adrenoceptors subtypes involved). Since trigeminal second-order wide dynamic range (WDR) cells are one of the main gatekeepers involved in decoding and processing nociceptive inputs from peripheral facial structures, this study was designed to test the effect of clonidine on trigeminal WDR cell activity in male and female rats. Methods Extracellular unitary recordings of trigeminal WDR cells were performed in anaesthetised Wistar rats and analysed as Aδ-, and C-fibres associated discharge. Under these conditions, the effect of local clonidine (3.1–31 nmol) on electrical periorbital-evoked firing of WDR cells was recorded in both sexes. Furthermore, considering that at least three α _2A adrenoceptor subtypes exist (α _2A -, α _2B - and α _2C -adrenoceptors), pharmacological blockade of these receptor subtypes was performed using BRL 44408 (α _2A ), imiloxan (α _2B ), and JP-1302 (α _2C ). Results Clonidine inhibited the activity of Aδ-, and C-fibres in male and female rats. This inhibition was observed in 50–60% of cells recorded. Furthermore, the dose necessary to induce similar electrophysiological antinociception was higher in females (31 nmol vs. 10 nmol). In males, but not females, clonidine-induced inhibition of Aδ- and C-fibres activity was reversed using BRL 44408. Whereas in females, imiloxan and JP-1302 reversed the clonidineinduced inhibition of Aδ- but not C-fibres. Conclusion Male rodents are more sensitive than females to clonidine-induced WDR antinociception. In males but not females, clonidine-induced inhibition of Aδ- and C-fibres discharge relies on α _2A -adrenoceptor activation. However, in females, the activation of α _2B/2C adrenoceptors seems to be relevant to Aδ- but not C-fibre discharge inhibition by clonidine, implying that other mechanism/receptors may be involved in females.

Article: Epidural oxytocin increases the quality of life and improves pain-associated symptom management in patients with terminal cancer - Minerva Anestesiologica 2024 May 22 - Minerva Medica - Journals

Migraine is a complex disorder, and its etiology is not yet fully understood. In the last 40 years, calcitonin gene-related peptide (CGRP) has been central to the understanding of migraine pathophysiology, leading to the development of new molecules targeting the CGRPergic system. These new molecules, such as gepants and monoclonal antibodies, are effective, well-tolerated, and safe, and are approved for clinical use. By searching multiple electronic scientific databases, this narrative review examined: (i) the role of CGRP in migraine; and (ii) the current knowledge on the effects of CGRPergic antimigraine pharmacotherapies, including a brief analysis of their pharmacodynamic and pharmacokinetic characteristics. Current anti-CGRPergic medications, although effective, have limitations, such as side effects and lack of antimigraine efficacy in some patients. The existence of patients with medication-resistant migraine may be due to the: (i) complex migraine pathophysiology, in which several systems appear to be deregulated before, during, and after a migraine attack; and (ii) pharmacodynamic and pharmacokinetic properties of antimigraine medications. As envisioned here, although seminal studies support the notion that CGRP plays a key role in migraine headache, the dysfunction of CGRPergic transmission does not seem to be relevant in all cases.

Oxytocinergic transmission blocks nociception at the peripheral, spinal, and supraspinal levels through the oxytocin receptor (OTR). Indeed, a neuronal pathway from the hypothalamic paraventricular nucleus (PVN) to the spinal cord and trigeminal nucleus caudalis (Sp5c) has been described. Hence, although the trigeminocervical complex (TCC), an anatomical area spanning the Sp5c, C1, and C2 regions, plays a role in some pain disorders associated with craniofacial structures (e.g., migraine), the role of oxytocinergic transmission in modulating nociception at this level has been poorly explored. Hence,in vivoelectrophysiological recordings of TCC wide dynamic range (WDR) cells sensitive to stimulation of the periorbital or meningeal region were performed in male Wistar rats. PVN electrical stimulation diminished the neuronal firing evoked by periorbital or meningeal electrical stimulation; this inhibition was reversed by OTR antagonists administered locally. Accordingly, neuronal projections (using fluoro-ruby) from the PVN to the WDR cells filled with neurobiotin were observed. Moreover, colocalization between OTR and CGRP or OTR and GABA was found near neurobiotin-filled WDR cells. Retrograde neuronal tracers deposited at the meningeal (true-blue) and infraorbital nerves (fluoro-gold) showed that at the trigeminal ganglion (TG), some cells were immunopositive to both fluorophores, suggesting that some TG cells send projections via the V1 and V2 trigeminal branches. Together, these data may imply that endogenous oxytocinergic transmission inhibits the nociceptive activity of second-order neurons via OTR activation in CGRPergic (primary afferent fibers) and GABAergic cells.Significance statementThis study sheds light on the mechanisms involved in the regulation of trigeminal nociception, which is crucial for understanding the pathophysiology of primary headaches, such as migraine. Current evidence suggests that the hypothalamus plays a role in controlling the nociceptive activity at the trigeminal level. The present study found that electrical stimulation of the hypothalamic paraventricular nucleus (PVN) inhibited the nociceptive activity of trigeminal second-order WDR cells through oxytocinergic mechanisms. Furthermore, we found that oxytocin receptors are located in the primary peptidergic afferent fibers and GABAergic cells. These findings support the idea of a direct oxytocinergic pathway between the PVN and TCC and highlight the potential of oxytocin receptors as a target for migraine pain and other primary headaches.