title: Orexin-A modulates glutamatergic NMDA-dependent spinal reflex potentiation via inhibition of NR2B subunit.
abstract: Glucose-sensitive neurons in the lateral hypothalamic area produce orexin-A (OxA) as well as orexin-B (OxB) and send their axons to the spinal dorsal horn, which predominantly expresses orexin receptor-1 (OX-1), showing a higher sensitivity to OxA. The purpose of the present study was to assess the effects of OxA on the induction of a novel form of activity-dependent reflex potentiation, spinal reflex potentiation (SRP), in the pelvic-urethral reflex activity. External urethra sphincter electromyogram in response to pelvic afferent nerve test stimulation (TS; 1/30 Hz) or repetitive stimulation (RS; 1 Hz) was recorded in anesthetized rats. TS evoked a baseline reflex activity, whereas RS produced SRP, which was abolished by intrathecal OxA (30 nM, 10 mul). Intrathecal SB-408124 (10 muM, 10 mul), an OX-1 antagonist, reversed the abolition on SRP caused by OxA. Although there is, so far, no NR2A- and NR2B-specific agonist available, N-methyl-d-aspartate (NMDA) reversed the abolition on the RS-induced SRP caused by the co-administration of OxA and Co-101244 (30 nM, 10 mul; an NMDA NR2B subunit antagonist), but it did not reverse the abolition by the co-administration of OxA and PPPA (300 nM, 10 mul; an NMDA NR2A subunit antagonist). In conclusion, the activation of descending orexinergic fibers may inhibit the repetitive afferent input-induced central sensitization of pelvic-urethral reflex activity and urethra hyperactivity, indicating that spinal orexinergic neural transmission may be a novel target for the treatment of patients with neuropathetic or postinflammatory pain of pelvic origin.
authors.affiliation: Department of Physiology, College of Medicine, Chung-Shan Medical University Hospital, 110, Chang-Kuo North Rd., Section 1, Taichung, Taiwan .
authors.forename: Hsien-Yu
authors.initials: HY
authors.lastname: Peng
authors.forename: Hung-Ming
authors.initials: HM
authors.lastname: Chang
authors.forename: Sarah Y
authors.initials: SY
authors.lastname: Chang
authors.forename: Kwong-Chung
authors.initials: KC
authors.lastname: Tung
authors.forename: Shin-Da
authors.initials: SD
authors.lastname: Lee
authors.forename: Dylan
authors.initials: D
authors.lastname: Chou
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Lai
authors.forename: Chun-Hsien
authors.initials: CH
authors.lastname: Chiu
authors.forename: Gin-Den
authors.initials: GD
authors.lastname: Chen
authors.forename: Tzer-Bin
authors.initials: TB
authors.lastname: Lin
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004576:Electromyography; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000494:pharmacology*; D000068797:Orexins; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012018:Reflex / Q000187:drug effects* / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects; D014521:Urethra / Q000187:drug effects / Q000294:innervation
chemical_list: D018691:Excitatory Amino Acid Antagonists; D047908:Intracellular Signaling Peptides and Proteins; C121001:NR2B NMDA receptor; D009479:Neuropeptides; D000068797:Orexins; D010879:Piperazines; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C065286:SDZ EAA 494; D016202:N-Methylaspartate; C120799:PD 174494