PACAP in adult sensory neurons - implications in injury and pain

Abstract: The data presented in this thesis deal with the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) in adult sensory neurons. We have used different injury and pain models to determine the involvement of PACAP during such conditions. The role of neurotrophins for PACAP expression was also investigated. PACAP is one of the excitatory neuropeptides expressed in small sized DRG neurons. The level of PACAP expression in such neurons is increased following peripheral inflammation but is decreased following sciatic nerve injury and instead induced in medium to large sized neurons. Data showed that under normal conditions and upon peripheral inflammation PACAP mRNA was expressed in trkA positive DRG L5 neurons. Intrathecally applied NGF dramatically increased both the number and the level of PACAP mRNA expression in small to medium sized neurons. The increased expression of PACAP after peripheral inflammation was inhibited by anti-NGF treatment. Hence, NGF seems to be a strong positive regulator of PACAP expression and appears to be responsible for the increased levels of PACAP expression during inflammation. In the formalin test, mice lacking the PACAP preferring receptor, PAC1 had a profoundly decreased nociceptive response in the late, inflammatory phase suggesting that the PAC1 receptor is important in the mediation of inflammatory pain. Intrathecally applied NT-3 reduced PACAP expression in intact neurons. Thus, while NGF appears to promote PACAP expression NT-3 appears to antagonise it. The dramatic increase of PACAP expression following nerve injury occurs in trkC positive, medium to large sized neurons and can be effectively mitigated by NT-3 and to a lesser degree by NGF. PAC1-/- mice had greater injury-induced changes in the expression of other neuropeptides, especially galanin, implying neuroregulatory functions of the PAC1 receptor after injury.