title: Role of Pituitary Adenylate-Cyclase Activating Polypeptide and Tac1 gene derived tachykinins in sensory, motor and vascular functions under normal and neuropathic conditions.
abstract: Pituitary Adenylate-Cyclase Activating Polypeptide (PACAP) and Tac1 gene-encoded tachykinins (substance P: SP, neurokinin A: NKA) are expressed in capsaicin-sensitive nerves, but their role in nociception, inflammation and vasoregulation is unclear. Therefore, we investigated the function of these neuropeptides and the NK1 tachykinin receptor (from Tacr1 gene) in the partial sciatic nerve ligation-induced traumatic mononeuropathy model using gene deficient (PACAP(-/-), Tac1(-/-), and Tacr1(-/-)) mice. Mechanonociceptive threshold of the paw was measured with dynamic plantar aesthesiometry, motor coordination with Rota-Rod and cutaneous microcirculation with laser Doppler imaging. Neurogenic vasodilation was evoked by mustard oil stimulating sensory nerves. In wildtype mice 30-40% mechanical hyperalgesia developed one week after nerve ligation, which was not altered in Tac1(-/-) and Tacr1(-/-) mice, but was absent in PACAP(-/-) animals. Motor coordination of the PACAP(-/-) and Tac1(-/-) groups was significantly worse both before and after nerve ligation compared to their wildtypes, but it did not change in Tacr1(-/-) mice. Basal postoperative microcirculation on the plantar skin of PACAP(-/-) mice did not differ from the wildtypes, but was significantly lower in Tac1(-/-) and Tacr1(-/-) ones. In contrast, mustard oil-induced neurogenic vasodilation was significantly smaller in PACAP(-/-) mice, but not in Tacr1(-/-) and Tac1(-/-) animals. Both PACAP and SP/NKA, but not NK1 receptors participate in normal motor coordination. Tachykinins maintain basal cutaneous microcirculation. PACAP is a crucial mediator of neuropathic mechanical hyperalgesia and neurogenic vasodilation. Therefore identifying its target and developing selective, potent antagonists, might open promising new perspectives for the treatment of neuropathic pain and vascular complications.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, H-7624 Pécs, Szigeti u. 12, Hungary.
authors.forename: Bálint
authors.initials: B
authors.lastname: Botz
authors.forename: András
authors.initials: A
authors.lastname: Imreh
authors.forename: Katalin
authors.initials: K
authors.lastname: Sándor
authors.forename: Krisztián
authors.initials: K
authors.lastname: Elekes
authors.forename: János
authors.initials: J
authors.lastname: Szolcsányi
authors.forename: Dóra
authors.initials: D
authors.lastname: Reglődi
authors.forename: John P
authors.initials: JP
authors.lastname: Quinn
authors.forename: James
authors.initials: J
authors.lastname: Stewart
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Helyes
mesh_terms: D000818:Animals; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015320:Tachykinins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018040:Receptors, Neurokinin-1; D015320:Tachykinins