Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is a naturally occurring neuropeptide found throughout the body. It belongs to a family of signaling molecules that influence various physiological processes, particularly within the nervous system and in response to stress. PACAP’s widespread distribution and diverse functions, including roles in neuronal signaling, blood vessel dilation, and immune system modulation, are significant. Recent research increasingly points to PACAP’s role in understanding and potentially treating migraine headaches, suggesting it contributes to the mechanisms that initiate and sustain migraine attacks.
What is PACAP and its Role in Migraine
PACAP was discovered over 30 years ago and exists in two main forms: PACAP-38 and PACAP-27, with PACAP-38 being the more extensively studied form in migraine research. It is widely distributed in the nervous system, including the trigeminal ganglion, nucleus caudalis of the trigeminal nerve, and the hypothalamus, where it acts as a neurotransmitter. PACAP receptors, particularly PAC1, VPAC1, and VPAC2, are present in these areas, as well as in cerebral blood vessels, all of which are implicated in migraine pathophysiology.
The involvement of PACAP in migraine is supported by studies showing that intravenous infusion of PACAP-38 can induce migraine-like attacks in individuals with a history of migraine. These induced attacks often present with typical migraine symptoms, including headache, light sensitivity, and nausea, and can have a delayed onset, sometimes hours after infusion, suggesting a sustained effect on migraine pain pathways.
PACAP contributes to migraine pathophysiology through several mechanisms. It is a potent vasodilator, causing the widening of blood vessels, particularly extracranial arteries, which may contribute to headache pain during a migraine attack. While vasodilation of cranial blood vessels was once thought to be the sole cause of migraine pain, current understanding suggests a more complex interplay, with PACAP’s vasodilatory effect being one contributing factor.
Beyond vasodilation, PACAP is involved in pain transmission pathways. It activates sensory nerves innervating the cranial vasculature, contributing to pain during migraine attacks. Research indicates PACAP can cause both peripheral and central sensitization of the trigeminovascular system, a nerve and blood vessel network implicated in migraine. This sensitization amplifies pain signals, leading to heightened sensitivity often experienced by migraine sufferers.
PACAP levels in the body also show changes during migraine attacks. Elevated PACAP levels have been detected in the blood of migraine sufferers during an attack, decreasing after successful acute treatment with medications like sumatriptan. This fluctuation in PACAP levels further supports its role in the active phase of a migraine and suggests its potential as a biomarker for primary headaches. The link between PACAP and chronic migraine is also being explored, with some evidence suggesting that lower interictal (between attacks) PACAP levels may be negatively correlated with the duration of migraine disease in adults.
PACAP Compared to CGRP
Calcitonin Gene-Related Peptide (CGRP) is another neuropeptide extensively studied for its role in migraine, and treatments targeting CGRP have significantly advanced migraine therapy. Both PACAP and CGRP are vasodilatory peptides capable of inducing migraine-like attacks when infused into individuals with migraine. They both contribute to pain signaling and are found in overlapping areas relevant to migraine, such as the trigeminal ganglion.
Despite these similarities, PACAP and CGRP have distinct receptor pathways and potentially different roles in the overall migraine cascade. CGRP primarily acts through the CGRP receptor, while PACAP exerts its effects through three G protein-coupled receptors: PAC1, VPAC1, and VPAC2, with PAC1 showing a much higher affinity for PACAP-38. Activation of both CGRP and PACAP receptors leads to an increase in cyclic adenosine monophosphate (cAMP) levels, which further activates protein kinase A (PKA).
A notable clinical difference is that PACAP, but not CGRP, has been observed to cause premonitory symptoms in patients. Furthermore, while both can cause vasodilation, PACAP-induced vasodilation, particularly of extracranial arteries, tends to be more prolonged than that caused by vasoactive intestinal peptide (VIP), a related neuropeptide that does not consistently induce migraine attacks.
Targeting PACAP might offer a unique or complementary approach to migraine treatment compared to existing CGRP-targeted therapies because the PACAP pathway appears to operate independently of the CGRP pathway. This suggests that PACAP and CGRP may contribute to migraine through parallel, rather than identical, mechanisms. For individuals who do not respond adequately to CGRP-blocking drugs, targeting PACAP could provide an alternative therapeutic option, potentially addressing different underlying mechanisms of their migraine.
Future Treatments Targeting PACAP
Given PACAP’s established role in migraine pathophysiology, current research and development efforts are focused on developing therapies that target PACAP or its receptors. Strategies involve using PACAP receptor antagonists, which block PACAP’s action at its receptors (particularly PAC1), or developing antibodies to directly bind and neutralize PACAP, preventing receptor activation.
Early clinical trials have explored these approaches. For instance, a monoclonal antibody directed against the PAC1 receptor showed no statistically significant benefit in preventing migraine in a phase 2a study. However, a different humanized monoclonal antibody, Lu AG09222, which targets the PACAP ligand (the peptide itself), demonstrated promising results in a phase 2 trial. A single intravenous dose of 750 mg of Lu AG09222 reduced monthly migraine days by an average of 6.2 days, compared to 4.2 days with placebo over a four-week period.
These are emerging areas of research, and the long-term safety and effectiveness of PACAP-targeted therapies are still under investigation. While the initial results for anti-PACAP antibodies are encouraging, particularly for patients who have not found relief with existing treatments, further studies, including larger phase 3 trials, are necessary to confirm their clinical utility. The potential for these treatments to address distinct migraine mechanisms offers hope for expanding therapeutic options for those living with this often debilitating condition.