Orexin-A modulates glutamatergic NMDA-dependent spinal reflex potentiation via inhibition of NR2B subunit.
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.
Peng
Hsien-Yu
HY
Department of Physiology, College of Medicine, Chung-Shan Medical University Hospital, 110, Chang-Kuo North Rd., Section 1, Taichung, Taiwan .
Chang
Hung-Ming
HM
Chang
Sarah Y
SY
Tung
Kwong-Chung
KC
Lee
Shin-Da
SD
Chou
Dylan
D
Lai
Cheng-Yuan
CY
Chiu
Chun-Hsien
CH
Chen
Gin-Den
GD
Lin
Tzer-Bin
TB
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
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