PACAP-38 related modulation of the cranial parasympathetic projection: A novel mechanism and therapeutic target in severe primary headache

Background and PurposeLittle is known of how cranial autonomic symptoms (CAS) in cluster headache and migraine may contribute to their severe headache phenotype. This strong association suggests the involvement of the cranial parasympathetic efferent pathway. To investigate its contribution, we studied the role of pituitary adenylate cyclase activating polypeptide-38 (PACAP-38), a potent sensory and parasympathetic neuropeptide, in modulating pre- and post-ganglionic cranial parasympathetic projection neurons, and their influence on headache-related trigeminal-autonomic responses.Experimental ApproachUsing PACAP-38 and PACAP-38 responsive receptor antagonists, electrophysiological, behavioural and facial neurovascular-blood flow was measured in rats to probe trigeminal- and parasympathetic-neuronal, periorbital thresholds and cranial-autonomic outcomes, as they relate to primary headaches.Key ResultsSumatriptan attenuated the development of PACAP-38 mediated activation and sensitization of trigeminocervical neurons and related periorbital allodynia. PACAP-38 also caused activation and enhanced responses of dural-responsive pre-ganglionic pontine-superior salivatory parasympathetic neurons. Further, the PACAP-38 responsive receptor antagonists dissected a role of VPAC1 and PAC1 receptors in attenuating cranial-autonomic and trigeminal-neuronal responses to activation of the cranial parasympathetic projection, which requires post-ganglionic parasympathetic neurotransmission.Conclusion and ImplicationsGiven the prevailing view that sumatriptan acts to some degree via a peripheral mechanism, our data support that PACAP-38 mediated receptor activation modulates headache-related cranial-autonomic and trigeminovascular responses via peripheral and central components of the cranial parasympathetic projection. This provides a mechanistic rationale for the association of CAS with more severe headache phenotypes in cluster headache and migraine, and supports the cranial parasympathetic projection as a potential novel locus for treatment by selectively targeting PACAP-38 or PACAP-38 responsive VPAC1/PAC1 receptors.