An outlook on the trigeminovascular mechanisms of action and side effects concerns of some potential neuropeptidergic antimigraine therapies.

Introduction: In addition to serotonin (5-hydroxytryptamine; 5-HT) and other (neuro)mediators, the role of neuropeptides in migraine pathophysiology is relevant. Indeed, while some molecules interfering with calcitonin gene-related peptide (CGRP) transmission have recently been approved for clinical antimigraine use, other neuropeptides with translational use are in the pipeline. Among others, hypothalamic neuropeptides such as pituitary adenylate cyclase-activating peptide (PACAP), oxytocin (OT), and orexins stand out as potential novel targets to treat this neurovascular disorder. Areas covered: Based on the aforementioned findings, the present review: (i) summarizes the current knowledge on the role of the above neuropeptides in the trigeminovascular system, and migraine pathophysiology; and (ii) discusses some issues related with the mechanisms of action and side effects concerns that could be elicited when targeting the CGRPergic, PACAPergic, oxytocinergic and orexinergic systems. Expert opinion: Specific antimigraine pharmacotherapies have evolved from the enhancement of serotonergic 5-HT1B/1D/1F transmission to the use of compounds interacting with neuropeptidergic systems. Canonically, neuropeptides cause an array of complex intracellular mechanisms that, after modifying neuronal and/or vascular transmission, result in antimigraine action and also potential side effects. Furthermore, due to the chemical nature of some molecules targeting the above neuropeptidergic transmission (e.g., monoclonal antibodies, peptides), there are some limiting pharmacokinetics issues.

The locus of Action of CGRPergic Monoclonal Antibodies Against Migraine: Peripheral Over Central Mechanisms.

Migraine is a complex neurovascular disorder characterized by attacks of moderate to severe unilateral headache, accompanied by photophobia among other neurological signs. Although an arsenal of antimigraine agents is currently available in the market, not all patients respond to them. As Calcitonin Gene-Related Peptide (CGRP) plays a key role in the pathophysiology of migraine, CGRP receptor antagonists (gepants) have been developed. Unfortunately, further pharmaceutical development (for olcegepant and telcagepant) was interrupted due to pharmacokinetic issues observed during the Randomized Clinical Trials (RCT). On this basis, the use of monoclonal antibodies (mAbs; immunoglobulins) against CGRP or its receptor has recently emerged as a novel pharmacotherapy to treat migraines. RCT showed that these mAbs are effective against migraines producing fewer adverse events. Presently, the U.S. Food and Drug Administration approved four mAbs, namely: (i) erenumab; (ii) fremanezumab; (iii) galcanezumab; and (iv) eptinezumab. In general, specific antimigraine compounds exert their action in the trigeminovascular system, but the locus of action (peripheral vs. central) of the mAbs remains elusive. Since these mAbs have a molecular weight of ∼150 kDa, some studies rule out the relevance of their central actions as they seem unlikely to cross the Blood-Brain Barrier (BBB). Considering the therapeutic relevance of this new class of antimigraine compounds, the present review has attempted to summarize and discuss the current evidence on the probable sites of action of these mAbs.

Inhibition of nociceptive dural input to the trigeminocervical complex through oxytocinergic transmission.

Migraine is a complex brain disorder that involves abnormal activation of the trigeminocervical complex (TCC). Since an increase of oxytocin concentration has been found in cerebrospinal fluid in migrainous patients and intranasal oxytocin seems to relieve migrainous pain, some studies suggest that the hypothalamic neuropeptide oxytocin may play a role in migraine pathophysiology. However, it remains unknown whether oxytocin can interact with the trigeminovascular system at TCC level. The present study was designed to test the above hypothesis in a well-established electrophysiological model of migraine. Using anesthetized rats, we evaluated the effect of oxytocin on TCC neuronal activity in response to dural nociceptive trigeminovascular activation. We found that spinal oxytocin significantly reduced TCC neuronal firing evoked by meningeal electrical stimulation. Furthermore, pretreatment with L-368,899 (a selective oxytocin receptor antagonist, OTR) abolished the oxytocin-induced inhibition of trigeminovascular neuronal responses. This study provides the first direct evidence that oxytocin, probably by OTR activation at TCC level inhibited dural nociceptive-evoked action potential in this complex. Thus, targeting OTR at TCC could represent a new avenue to treat migraine.

Oxytocin inhibits the rat medullary dorsal horn Sp5c/C1 nociceptive transmission through OT but not V1A receptors.

The medullary dorsal horn (MDH or Sp5c/C1 region) plays a key role modulating the nociceptive input arriving from craniofacial structures. Some reports suggest that oxytocin could play a role modulating the nociceptive input at the MDH level, but no study has properly tested this hypothesis. Using an electrophysiological and pharmacological approach, the present study aimed to determine the effect of oxytocin on the nociceptive signaling in the MDH and the receptor involved. In sevoflurane, anesthetized rats, we performed electrophysiological unitary recordings of second order neurons at the MDH region responding to peripheral nociceptive-evoked responses of the first branch (V1; ophthalmic) of the trigeminal nerve. Under this condition, we constructed dose-response curves analyzing the effect of local spinal oxytocin (0.2-20 nmol) on MDH nociceptive neuronal firing. Furthermore, we tested the role of oxytocin receptors (OTR) or vasopressin V1A receptors (V1AR) involved in the oxytocin effects. Oxytocin dose-dependently inhibits the peripheral-evoked activity in nociceptive MDH neurotransmission. This inhibition is associated with a blockade of neuronal activity of Aδ- and C-fibers. Since this antinociception was abolished by pretreatment (in the MDH) with the potent and selective OTR antagonist (L-368,899; 20 nmol) and remained unaffected after the V1AR antagonist (SR49059; 20 nmol or 200 nmol), the role of OTR is implied. This electrophysiological study demonstrates that oxytocin inhibits the peripheral-evoked neuronal activity at MDH, through OTR activation. Thus, OTR may represent a new potential drug target to treat craniofacial nociceptive dysfunction in the MDH.