Aims: 

Pituitary adenylate-cyclase activating polypeptide (PACAP) and its receptors are present in the brainstem, spinal dorsal horn, capsaicin-sensitive sensory neurons and vascular smooth muscle. Data concerning its involvement in pain are controversial. Recent studies suggested its role in triggering migraine in humans. Therefore, we investigated its function in a variety of mouse pain models.

Methods: 

Formalin-evoked acute somatic and acetic acid-induced visceral nocifensive behaviors, partial sciatic nerve ligation-evoked neuropathic, as well as resiniferatoxin-induced inflammatory mechanical and thermal hyperalgesia were examined in PACAP deficient (PACAP^-/-) and wild type mice. Nitroglycerol-induced trigeminovascular activation, related to migraine, was also studied with behavioural and vascular imaging techniques. C-fos, as an early marker of neuronal activation was examined with immunohistochemistry in respective brain regions.

Results: 

Formalin-evoked paw lickings and acetic acid-evoked abdominal contractions were significantly attenuated, and neuropathic mechanical hyperalgesia was absent in PACAP-deleted mice. Resiniferatoxin-evoked mechanical hyperalgesia involving central sensitization was decreased, but thermal hyperalgesia mediated by peripheral mechanisms was increased in the PACAP^-/- group. Decreased c-fos expression was found in the periaqueductal grey and somatosensory cortex of PACAP^-/- animals. Nitroglycerol evoked reduced light-aversive behavior, meningeal vasodilatation and c-Fos expression in the trigeminal ganglia and nucleus in case of PACAPdeletion.

Conclusion: 

The overall role of PACAP in pain transmission originating from both exteroceptive and interoceptive areas is stimulatory. It is an important excitatory mediator of central sensitization and trigeminovascular activation related to migraine-like headaches. In contrast, it has an inhibitory effect at the periphery.

Support: 

OTKA K72592, K73044, ETT 03-380/2009, SROP-4.2.1.B-10/2/KONV-2010-0002