title: Vagal afferents are necessary for the establishment but not the maintenance of kainic acid-induced hyperalgesia in mice.
abstract: Systemic administration of a single, sub-convulsive dose (20mg/kg) of kainic acid (KA) produces long-term hyperalgesia. The robustness and reproducibility of this effect makes this a valuable model of chronic pain. However, the mechanism by which KA produces hyperalgesia remains unknown. We evaluated the role of vagal afferents on KA-induced hyperalgesia in mice by assessing the influence of bilateral subdiaphragmatic vagotomy and of direct application of KA to vagal afferents on the development of hyperalgesia. The hot plate and tail flick tests were used to assess pain behavior. Central nervous system (CNS) activity evoked by acute administration of KA or exposure to a nociceptive stimulus was also determined by the immunocytochemical detection of Fos and of phosphorylated extracellular signal-regulated protein kinases 1 and 2 (pErk). Mice exhibited a persistent hyperalgesia after either systemic application of KA or topical treatment with KA on vagal afferents. Vagotomy performed 2 weeks before the application of KA was able to prevent the establishment of hyperalgesia, but vagotomy performed 2 weeks after the application of KA was unable to reverse the already established hyperalgesia. This result establishes that vagal afferents are pivotal to the onset of hyperalgesia. Consistent with this, KA evoked the expression of Fos in vagal related areas of the brainstem, including the nucleus tractus solitarius (NTS) and area postrema (AP), as well as widespread areas of the forebrain. Vagotomy selectively decreased KA-evoked Fos in the NTS while sparing that in other brain areas. In addition to hyperalgesia, weeks after KA treatment, stimulus induced pErk was increased in spinal nociceptive neurons and the medial hypothalamus, a phenomenon that was prevented by prior vagotomy. No signs of cell death were detected using in situ nick end-labeling (TUNEL) assay and Nissl staining at 1, 5, 24, 36 h and 12 days post-KA. These findings suggest that the mechanism underlying KA-induced hyperalgesia is a long-term dysfunction of CNS areas that are activated by vagal afferents and involved in descending control of spinal nociceptive neurons.
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, 505 Parnassus, Box 0112, San Francisco, CA 94143, USA.
authors.forename: Duc
authors.initials: D
authors.lastname: Tien
authors.forename: Peter T
authors.initials: PT
authors.lastname: Ohara
authors.forename: Alice A
authors.initials: AA
authors.lastname: Larson
authors.forename: Luc
authors.initials: L
authors.lastname: Jasmin
mesh_terms: D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling / Q000379:methods; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020928:Mitogen-Activated Protein Kinases / Q000145:classification / Q000378:metabolism; D009475:Neurons, Afferent / Q000502:physiology*; D009620:Nodose Ganglion / Q000166:cytology; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010147:Pain Measurement; D013116:Spinal Cord / Q000033:anatomy & histology / Q000378:metabolism; D014628:Vagotomy; D014630:Vagus Nerve / Q000502:physiology*
chemical_list: D016761:Oncogene Proteins v-fos; D020928:Mitogen-Activated Protein Kinases; D007608:Kainic Acid