title: Chronic activation of sigma-1 receptor evokes nociceptive activation of trigeminal nucleus caudalis in rats.
abstract: Primary headache disorders, including migraine, are thought to be mediated by prolonged nociceptive activation of the trigeminal nucleus caudalis (TNC), but the precise mechanisms are poorly understood. Our past studies demonstrated that sigma-1 receptors (Sig-1R) facilitate spinal nociceptive transmission in several pain models. Based on these findings, this study asked if chronic activation of Sig-1R by intracisternal administration of the selective Sig-1R agonist, PRE084, produced TNC neuronal activation as a migraine trigger in rats. A single infusion of PRE084 (10, 50, 100, 500 nmol) significantly increased the number of Fos immunoreactive neurons (Fos-IR) in TNC, which BD1047 (a Sig-1R antagonist) reversed. Chronic infusion of PRE084 (100 nmol for 1, 3, 7 and 14 days) time-dependently elevated Fos-IR in TNC. The number of Fos-IR elevation from day 7 of infusion was comparable with a single capsaicin infusion as a headache model. Increase in face grooming/scratching behavior was evident from day 7, and peaked at day 14 of chronic PRE084 infusion, which was correlated with ΔFosB elevation and phosphorylation of extracellular signal-regulated kinase, and the NMDA receptor NR1 subunit in TNC. Following 14 days of PRE084 infusion, the number of Fos-IR increased until day 7 after final infusion. Moreover, by day 14, Fos-IR associated with PRE084 infusion was significantly reversed by NMDA receptor antagonist MK801, rather than BD1047. These findings indicated that chronic activation of Sig-1R could evoke prolonged neuronal activation in the trigeminovascular system.
authors.affiliation: Department of Computer Science and Engineering, Chonbuk National University, Jeonju 561-180, Republic of Korea.
authors.forename: Kihyun
authors.initials: K
authors.lastname: Pyun
authors.affiliation: Department of Anesthesiology and Pain Medicine, Chonbuk National University Medical School, Jeonju 561-180, Republic of Korea.
authors.forename: Ji Seon
authors.initials: JS
authors.lastname: Son
authors.affiliation: Department of Pharmacology, Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Republic of Korea. Electronic address: 1972y@jbnu.ac.kr.
authors.forename: Young Bae
authors.initials: YB
authors.lastname: Kwon
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002211:Capsaicin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000008:administration & dosage* / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D014278:Trigeminal Nuclei / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000097605:Sigma-1 Receptor
chemical_list: D002211:Capsaicin; D009025:Morpholines; D016760:Proto-Oncogene Proteins c-fos; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
keywords: Extracellular signal-regulated kinase; Fos; Migraine; NMDA receptor; Sigma-1 receptor; Trigeminal nucleus caudalis