Pro-nociceptive effects of neuromedin U in rat.
The neuropeptide neuromedin U (NMU) has been shown to have significant effects on cardiovascular, gastrointestinal and CNS functions. The peptide was first isolated from the porcine spinal cord and later shown to be present in spinal cords of other species. Little is known about the distribution of neuromedin U receptors (NMURs) in the spinal cord and the spinal action of the peptide. Here we report on the expression of NMURs and a potential role in nociception in the rat spinal cord using a combination of behavioral and electrophysiological studies. Receptor autoradiography showed that NMU-23 binding was restricted to the superficial layers of spinal cord, a region known to be involved in the control of nociception. In situ hybridization analysis indicated the mRNA of NMUR2 was located in the same region (laminae I and IIo) as NMU-23 binding, while the mRNA for NMU receptor 1 was observed in a subpopulation of small diameter neurons of dorsal root ganglia. Intrathecal (i.t.) administration of neuromedin U-23 (0.4-4.0 nmol/10 microl) dose-dependently decreased both the mechanical threshold to von Frey hair stimulation and the withdrawal latency to a noxious thermal stimulus. Mechanical allodynia was observed between 10 and 120 min, peaking at 30 min and heat hyperalgesia was observed 10-30 min after i.t. administration of NMU-23. A similar mechanical allodynia was also observed following i.t. administration of NMU-8 (0.4-4 nmol/10 microl). A significant enhancement of the excitability of flexor reflex was induced by intrathecal administration of NMU-23 (4 nmol/10 microl). Evoked responses to touch and pinch stimuli were increased by 439+/-94% and 188+/-36% (P<0.01, n=6) respectively. The behavioral and electrophysiological data demonstrate, for the first time, a pro-nociceptive action of NMU. The restricted distribution of NMU receptors to a region of the spinal cord involved in nociception suggests that this peptide receptor system may play a role in nociception.
Yu
X H
XH
AstraZeneca Research and Development Montreal, 7171 Frederick-Banting, St. Laurent, Montreal, Quebec, Canada H4S 1Z9. xiaohong.yu@astrazeneca.com
Cao
C Q
CQ
Mennicken
F
F
Puma
C
C
Dray
A
A
O'Donnell
D
D
Ahmad
S
S
Perkins
M
M
D000818:Animals; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology / Q000379:methods; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008297:Male; D008565:Membrane Proteins; D009043:Motor Activity / Q000187:drug effects; D009479:Neuropeptides / Q000009:adverse effects* / Q000145:classification; D010146:Pain / Q000139:chemically induced*; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D010812:Physical Stimulation / Q000379:methods; D016372:RNA, Antisense; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013552:Swine; D013997:Time Factors
D007456:Iodine Isotopes; D008565:Membrane Proteins; D009479:Neuropeptides; D010446:Peptide Fragments; D016372:RNA, Antisense; D012333:RNA, Messenger; D017981:Receptors, Neurotransmitter; C082444:neuromedin U receptor; C056900:neuromedin U