title: Impaired nocifensive behaviours and mechanical hyperalgesia, but enhanced thermal allodynia in pituitary adenylate cyclase-activating polypeptide deficient mice.
abstract: Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and its receptors (PAC1 and VPAC) have been shown in the spinal dorsal horn, dorsal root ganglia and sensory nerve terminals. Data concerning the role of PACAP in central pain transmission are controversial and we have recently published its divergent peripheral effects on nociceptive processes. The aim of the present study was to investigate acute somatic and visceral nocifensive behaviours, partial sciatic nerve ligation-evoked chronic neuropathic, as well as resiniferatoxin-induced inflammatory thermal and mechanical hyperalgesia in PACAP deficient (PACAP(-/-)) mice to elucidate its overall function in pain transmission. Neuronal activation was investigated with c-Fos immunohistochemistry. Paw lickings in the early (0-5 min) and late (20-45 min) phases of the formalin test were markedly reduced in PACAP(-/-) mice. Acetic acid-evoked abdominal contractions referring to acute visceral chemonociception was also significantly attenuated in PACAP knockout animals. In both models, the excitatory role of PACAP was supported by markedly greater c-Fos expression in the periaqueductal grey and the somatosensory cortex. In PACAP-deficient animals neuropathic mechanical hyperalgesia was absent, while c-Fos immunopositivity 20 days after the operation was significantly higher. In this chronic model, these neurons are likely to indicate the activation of secondary inhibitory pathways. Intraplantarly injected resiniferatoxin-evoked mechanical hyperalgesia involving both peripheral and central processes was decreased, but thermal allodynia mediated by only peripheral mechanisms was increased in PACAP(-/-) mice. These data clearly demonstrate an overall excitatory role of PACAP in pain transmission originating from both exteroceptive and interoceptive areas, it is also involved in central sensitization. This can be explained by the signal transduction mechanisms of its identified receptors, both PAC1 and VPAC activation leads to neuronal excitation. In contrast, it is an inhibitory mediator at the level of the peripheral sensory nerve endings and decreases their sensitization to heat with presently unknown mechanisms.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Pécs, Pécs, Hungary.
authors.forename: K
authors.initials: K
authors.lastname: Sándor
authors.forename: V
authors.initials: V
authors.lastname: Kormos
authors.forename: B
authors.initials: B
authors.lastname: Botz
authors.forename: A
authors.initials: A
authors.lastname: Imreh
authors.forename: K
authors.initials: K
authors.lastname: Bölcskei
authors.forename: B
authors.initials: B
authors.lastname: Gaszner
authors.forename: A
authors.initials: A
authors.lastname: Markovics
authors.forename: J
authors.initials: J
authors.lastname: Szolcsányi
authors.forename: N
authors.initials: N
authors.lastname: Shintani
authors.forename: H
authors.initials: H
authors.lastname: Hashimoto
authors.forename: A
authors.initials: A
authors.lastname: Baba
authors.forename: D
authors.initials: D
authors.lastname: Reglodi
authors.forename: Z
authors.initials: Z
authors.lastname: Helyes
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009619:Nociceptors / Q000502:physiology*; D010147:Pain Measurement; D010487:Periaqueductal Gray / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013003:Somatosensory Cortex / Q000378:metabolism
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016760:Proto-Oncogene Proteins c-fos