Introduction: Migraine is a neurovascular disorder. Current acute specific antimigraine pharmacotherapies target trigeminovascular 5-HT_1B/1D, 5-HT_1F and CGRP receptors but, unfortunately, they induce some cardiovascular and central side effects that lead to poor treatment adherence/compliance. Therefore, new antimigraine drugs are being explored. Areas covered: This review considers the adverse (or potential) side effects produced by current and prospective antimigraine drugs, including medication overuse headache (MOH) produced by ergots and triptans, the side effects observed in clinical trials for the new gepants and CGRP antibodies, and a section discussing the potential effects resulting from disruption of the cardiovascular CGRPergic neurotransmission. Expert opinion: The last decades have witnessed remarkable developments in antimigraine therapy, which includes acute (e.g. triptans) and prophylactic (e.g. β-adrenoceptor blockers) antimigraine drugs. Indeed, the triptans represent a considerable advance, but their side effects (including nausea, dizziness and coronary vasoconstriction) preclude some patients from using triptans. This has led to the development of the ditans (5-HT_1F receptor agonists), the gepants (CGRP receptor antagonists) and the monoclonal antibodies against CGRP or its receptor. The latter drugs represent a new hope in the antimigraine armamentarium, but as CGRP plays a role in cardiovascular homeostasis, the potential for adverse cardiovascular side effects remains latent.

Background: Marijuana extracts (cannabinoids) have been used for several millennia for pain treatment. Regarding the site of action, cannabinoids are highly promiscuous molecules, but only two cannabinoid receptors (CB₁ and CB₂) have been deeply studied and classified. Thus, therapeutic actions, side effects and pharmacological targets for cannabinoids have been explained based on the pharmacology of cannabinoid CB₁/CB₂ receptors. However, the accumulation of confusing and sometimes contradictory results suggests the existence of other cannabinoid receptors. Different orphan proteins (e.g., GPR18, GPR55, GPR119, etc.) have been proposed as putative cannabinoid receptors. According to their expression, GPR18 and GPR55 could be involved in sensory transmission and pain integration. Methods: This article reviews select relevant information about the potential role of GPR18 and GPR55 in the pathophysiology of pain. Results: This work summarized novel data supporting that, besides cannabinoid CB₁ and CB₂ receptors, GPR18 and GPR55 may be useful for pain treatment. Conclusion: There is evidence to support an antinociceptive role for GPR18 and GPR55.

Oxytocin (OT) has emerged as a mediator of endogenous analgesia in behavioral and electrophysiological experiments. In fact, OT receptors (OTRs) in the spinal dorsal horn participate in a selective inhibition of the neuronal activity mediated by Aδ and C fibers but not Aβ fibers. This study shows that OTRs are expressed in the terminal nerve endings and are able to inhibit nociceptive neuronal firing. Indeed, local peripheral OT blocked the first sensorial activity of Aδ and C fibers recorded in the spinal cord neurons. Furthermore, using the formalin behavioral nociceptive test, we demonstrated that only ipsilateral OTR activation inhibits pain behavior. Our data are reinforced by the fact that the OTR protein is expressed in the sciatic nerve. Consistent with this, immunofluorescence of primary afferent fibers suggest that OTRs could be located in nociceptive-specific terminals of the skin. Taken together, our results suggest that OTRs could be found in nociceptive terminals and that on activation they are able to inhibit nociceptive input.

The rostral agranular insular cortex (RAIC) is a relevant structure in nociception. Indeed, recruitment of GABAergic activity in RAIC promotes the disinhibition of the locus ceruleus, which in turn inhibits (by noradrenergic action) the peripheral nociceptive input at the spinal cord level. In this regard, at the cortical level, oxytocin can modulate the GABAergic transmission; consequently, an interaction modulating nociception could exist between oxytocin and GABA at RAIC. Here, we tested in male Wistar rats the effect of oxytocin microinjection into RAIC during an inflammatory (by subcutaneous peripheral injection of formalin) nociceptive input. Oxytocin microinjection produces a diminution of (1) flinches induced by formalin and (2) spontaneous firing of spinal wide dynamic range cells. The above antinociceptive effect was abolished by microinjection (at RAIC) of the following: (1) L-368899 (an oxytocin receptor [OTR] antagonist) or by (2) bicuculline (a preferent GABA_A receptor blocker), suggesting a GABAergic activation induced by OTR. Since intrathecal injection of an α_2A-adrenoceptor antagonist (BRL 44408) partially reversed the oxytocin effect, a descending noradrenergic antinociception is suggested. Further, injection of L-368899 per se induces a pronociceptive behavioral effect, suggesting a tonic endogenous oxytocin release during inflammatory nociceptive input. Accordingly, we found bilateral projections from the paraventricular nucleus of the hypothalamus (PVN) to RAIC. Some of the PVN-projecting cells are oxytocinergic and destinate GABAergic and OTR-expressing cells inside RAIC. Aside from the direct anatomic link between PVN and RAIC, our findings provide evidence about the role of oxytocinergic mechanisms modulating the pain process at the RAIC level. SIGNIFICANCE STATEMENT Oxytocin is a neuropeptide involved in several functions ranging from lactation to social attachment. Over the years, the role of this molecule in pain processing has emerged, showing that, at the spinal level, oxytocin blocks pain transmission. The present work suggests that oxytocin also modulates pain at the cortical insular level by favoring cortical GABAergic transmission and activating descending spinal noradrenergic mechanisms. Indeed, we show that the paraventricular hypothalamicnucleus sends direct oxytocinergic projections to the rostral agranular insular cortex on GABAergic and oxytocin receptor-expressing neurons. Together, our data support the notion that the oxytocinergic system could act as an orchestrator of pain modulation.