Role of Pituitary Adenylate-Cyclase Activating Polypeptide and Tac1 gene derivedudtachykinins in sensory, motor and vascular functions under normal andudneuropathic conditions

摘要

Pituitary Adenylate-Cyclase Activating Polypeptide (PACAP) and Tac1 gene-encoded tachykinins (substanceudP: SP, neurokinin A: NKA) are expressed in capsaicin-sensitive nerves, but their role inudnociception, inflammation and vasoregulation is unclear. Therefore, we investigated the function of theseudneuropeptides and the NK1 tachykinin receptor (from Tacr1 gene) in the partial sciatic nerve ligationinducedudtraumatic mononeuropathy model using gene deficient (PACAP−/−, Tac1−/−, and Tacr1−/−) mice.udMechanonociceptive threshold of the paw was measured with dynamic plantar aesthesiometry, motorudcoordination with Rota-Rod and cutaneous microcirculation with laser Doppler imaging. Neurogenicudvasodilation was evoked by mustard oil stimulating sensory nerves. In wildtype mice 30–40% mechanicaludhyperalgesia developed one week after nerve ligation, which was not altered in Tac1−/− and Tacr1−/−udmice, but was absent in PACAP−/− animals. Motor coordination of the PACAP−/− and Tac1−/− groups wasudsignificantly worse both before and after nerve ligation compared to their wildtypes, but it did not changeudin Tacr1−/− mice. Basal postoperative microcirculation on the plantar skin of PACAP−/− mice did not differudfrom the wildtypes, but was significantly lower in Tac1−/− and Tacr1−/− ones. In contrast, mustardudoil-induced neurogenic vasodilation was significantly smaller in PACAP−/− mice, but not in Tacr1−/− andudTac1−/− animals. Both PACAP and SP/NKA, but not NK1 receptors participate in normal motor coordination.udTachykinins maintain basal cutaneous microcirculation. PACAP is a crucial mediator of neuropathicudmechanical hyperalgesia and neurogenic vasodilation. Therefore identifying its target and developingudselective, potent antagonists, might open promising new perspectives for the treatment of neuropathicudpain and vascular complications.