PACAP: A New Target for Treatment of Post-Traumatic Headache?

By Neil Andrews | January 8, 2024 | Posted in

A recent randomized clinical trial builds the case for pituitary adenylate cyclase-activating polypeptide-38 in the pathophysiology of PTH.

Post-traumatic headache (PTH) is a difficult clinical problem for which no specific treatments exist. Often the result of a traumatic brain injury (TBI), PTH can quickly become chronic and occur daily. A better understanding of the pathophysiological changes underlying PTH could lead the way to better therapies, and a new study now takes an important step toward that goal.

Researchers led by Håkan Ashina, Beth Israel Deaconess Medical Center, Boston, US, and Danish Headache Center, Copenhagen University Hospital, Denmark, report results from a randomized clinical trial of patients with PTH resulting from TBI. This small study of 21 people found that 95% of trial participants developed migraine-like headache in response to pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), a molecule perhaps better known for its role in migraine.

That such a large proportion of study participants experienced migraine-like headache in response to PACAP-38 suggests that this neuropeptide plays an important role in PTH pathophysiology – though exactly how remains unclear – and perhaps could serve as an attractive drug target.

Dan Levy, who studies PTH at Beth Israel Deaconess Medical Center but was not involved with the new research, said the main findings are “very interesting” but that it’s unclear if the human provocation model featured in the study, where the team used PACAP-38 to cause headache, captures what normally happens in people with PTH.

“I think this is a good paper that gives us important findings,” said Levy. However, “all the human provocation models infuse an agent with the idea of seeing whether it can trigger a migraine-like or a PTH-like attack, but we do not know whether this is actually mimicking something that goes on endogenously in patients.”

The research appeared online ahead of print on October 21, 2023, in Brain.

The impetus for a clinical trial
Ashina told Migraine Science Collaborative in an interview that the relationship between migraine and PTH, as well as the dearth of treatment options for the latter, spurred him and his colleagues to undertake the new trial.

“We were motivated by the clinical similarities between post-traumatic headache and migraine as well as the significant role that PACAP-38 appears to play in migraine pathogenesis. So, given the limited understanding and treatment options for post-traumatic headache, we saw it as an opportunity to explore whether PACAP-38 could be a common denominator in the pathogenesis and thereby, also, a potential therapeutic target,” Ashina said.

To test the idea, the researchers enrolled 21 people with persistent PTH resulting from a mild TBI, according to the 3rd edition of the International Classification of Headache Disorders (ICHD-3). Participants in this randomized, double-blind, placebo-controlled, crossover trial needed to have an average of at least four monthly headache days across the three months prior to enrolling in the study, with no history of a primary or secondary headache disorder before TBI.

The researchers infused intravenous PACAP-38 or placebo continuously for 20 minutes on the first experimental day, with 10 patients randomized to PACAP-38 and 11 to placebo.

After a wash-out period of at least seven days, participants would then take part in a second experimental day if they needed acute medication at least two days before the planned infusion start, had a baseline headache intensity of more than 3 on an 11-point numeric rating scale, or said they had migraine-like headache before the infusion start. Those who received PACAP-38 on experimental day 1 would receive placebo on day 2, and vice versa.

The main outcome measure of the trial was the difference in migraine-like headache incidence between those who received PACAP-38 and those who received a placebo, 12 hours after infusion.

Study flow diagram. n, number; PACAP-38, pituitary adenylate cyclase-activating polypeptide-38. Credit: Al-Khazali et al. Brain. 2023 Oct 21:awad367.


An almost universal response to PACAP-38
The results from the trial were striking. Of the trial’s 21 participants with PTH (who had an average age of 35 years; 76% were women), all but one (95%) reported a migraine-like headache after receiving PACAP-38, compared to just two (10%) in the placebo group, at 12 hours post-infusion.

“This proves that PACAP-38 is a potent inducer of migraine-like headache in post-traumatic headache patients. The surprising aspect was the effect size,” Ashina said, noting that he had expected that perhaps 60% to 70% of participants would experience migraine-like headache, rather than see the near-universal response the results indicated.

The investigators also discovered that those who received PACAP-38 had median headache intensity scores that were twice as high compared to the placebo group. Finally, the team also looked at hemodynamic variables. There was no difference between groups in terms of changes (from baseline) in mean arterial blood pressure, though those in the PACAP-38 group showed a greater change in heart rate.

What’s the mechanism?
In their paper, the authors explained their reasoning about how PACAP-38 may function to cause headache. While it’s possible that PACAP-38 could directly activate meningeal sensory neurons, or neurons in the trigeminocervical complex, the group argued that one or both of two indirect mechanisms are more likely to be involved.

One possibility is that PACAP-38 binds to its receptor on vascular smooth muscle cells, which sets in motion a signaling pathway resulting in the opening of potassium channels in those cells. Potassium then flows through these ion channels to cause vasodilation, leading to the indirect activation and sensitization of meningeal nociceptors. Exactly how vasodilation and potassium efflux activate the nociceptors remains unclear, but Ashina offered two scenarios.

“The dilation has two components: There is the mechanical aspect where dilation itself will stimulate the perivascular nociceptors, and the increase in positively charged potassium ions could provide electrochemical stimulation of the nociceptors.”

A second prospect involves mast cells. Here, the idea is that in response to PACAP-38, these immune system cells release histamine, a pro-nociceptive chemical agent that is known to induce migraine and also cluster headache. In that situation, the released histamine would bind to its receptor on vascular smooth muscle cells, resulting, as in the first scenario, in vasodilation and activation of meningeal nociceptors.

“Perhaps both mechanisms are in play,” Ashina said.

Levy cautioned that there is still no proof that vasodilation per se can activate meningeal nociceptors. “I don’t think we understand this yet, so we need to do a better job in trying to figure out if it’s vascular, or if it’s not vascular, or if it’s a combination of vascular and non-vascular factors.”

Levy was most enthusiastic about the potential role of mast cells in PTH. “Targeting mast cells maybe would be better [than targeting a single molecule] because mast cells are downstream [of PACAP-38 binding], they have receptors for many factors, and they can release a lot of inflammatory and pain mediators that could drive headaches.” Here, though, he emphasized that it is still unclear exactly how the mast cells themselves would differ from normal in the context of PTH.

Possible mechanisms and sites of action of PACAP-38-induced migraine-like headache in people with persistent PTH. The figure illustrates two possible sites of action of PACAP-38 induced migraine-like headache. (I) Indirect activation of meningeal nociceptors occurs through the dilation of intracranial arteries, accompanied by the potassium efflux from vascular smooth muscle cells. PACAP-38 binds to its G protein-coupled receptor in the vascular smooth muscle cell, initiating the cAMP-dependent signalling pathway. This pathway leads to the opening of KATP channels and BKCa channels, resulting in potassium efflux and subsequent vasodilation. These processes are hypothesized to activate and sensitize perivascular meningeal nociceptors through chemical and mechanical stimulation. (II) Indirect activation of meningeal nociceptors is mediated by mast cell degranulation and the release of pro-nociceptive chemical agents. PACAP-38 binds to its MrgX2 receptor in mast cells, causing degranulation of histamine and tryptase. Both histamine and tryptase bind to their respective G protein-coupled receptors on vascular smooth muscle cells, leading to vasodilation and activation of meningeal nociceptors, likely through a similar mechanism as described in scenario (I). PACAP-38, pituitary adenylate cyclase-activating polypeptide-38; PTH, post-traumatic headache; AC, adenylate cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; H2R, histamine receptor H2; KATP channels, ATP-sensitive potassium channels; BKCa channels, large conductance calcium-activated potassium channels. Credit: Al-Khazali et al. Brain. 2023 Oct 21:awad367.


Next steps
With regard to exactly how PACAP-38 is contributing to PTH, Ashina called for animal studies to learn more about the mechanisms. And it’s important to know what the mechanisms are, he said, to aid drug development efforts. For instance, he noted that basic science studies could help determine whether PACAP-38 is acting in the central nervous system or is instead working peripherally to cause migraine-like headache.

Future studies could also elucidate the relative contributions of PACAP-38 and calcitonin gene-related peptide (CGRP).

“We see so many similarities in terms of the physiological effects of CGRP and PACAP-38, so what I would encourage with our data is that people start to study, in concussed rodents, what would be the shared and different mechanisms among CGRP and PACAP in the context of post-traumatic headache. Because I think we could use the head trauma model in rodents to understand headache pathophysiology. And those findings could not only extend to post-traumatic headache but also beyond primary headache disorders,” Ashina said.

Whether PACAP-38 plays a similar role in spontaneous episodes of migraine-like headache that people with PTH often experience is also something that future studies could address.

For his part, Levy said that understanding how PTH becomes chronic is also important.

“The initial trauma obviously has a [time]-limited effect, but then something happens that makes the system become hyperexcitable. We don’t know what the chronification mechanism is,” according to Levy.

On the clinical side, Ashina noted promising findings from a recent human study of a monoclonal antibody against the PACAP ligand. Lundbeck, the company developing the drug, reported positive results from a Phase 2 trial in people with migraine. “And the next step, and the most important step, would likely be, if the Phase 3 trial with the anti-PACAP antibody is positive, to test it in these PTH patients.”

As the field awaits further data on the antibody, Ashina returned to the clinical need facing people with PTH.

“The key aspect here is to remember that post-traumatic headache is something that affects millions of people worldwide, but we have no evidence-based treatments. We need these kinds of drug discovery efforts and also additional animal studies to better understand the disease mechanisms.”

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative. Follow him on Twitter @NeilAndrews

Featured image credit: Photo 73449415 | Meninges © 7active Studio |

Hypersensitivity to PACAP-38 in post-traumatic headache: a randomized clinical trial.
Al-Khazali et al.
Brain. 2023 Oct 21:awad367. Online ahead of print.

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Neil Andrews is a science journalist and editor based in New York City. He has over two decades of experience covering science and medicine for expert and non-expert audiences alike. He is also the executive editor of the Migraine Science Collaborative, where he manages the day to day operations of the site. Previously he was the executive editor of the Pain Research Forum.

When not thinking and writing about neuroscience, Neil spends much of his free time on his Peloton and exploring NYC. He is also on a quest to satisfy his coffee cravings by visiting every independent coffee shop in the city. Follow him on Twitter @NeilAndrews.



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