Thermal nociception is decreased by hypocretin-1 and an adenosine A1 receptor agonist microinjected into the pontine reticular formation of Sprague Dawley rat.
Clinical and preclinical data concur that sleep disruption causes hyperalgesia, but the brain mechanisms through which sleep and pain interact remain poorly understood. Evidence that pontine components of the ascending reticular activating system modulate sleep and nociception encouraged the present study testing the hypothesis that hypocretin-1 (orexin-A) and an adenosine receptor agonist administered into the pontine reticular nucleus, oral part (PnO) each alter thermal nociception. Adult male rats (n = 23) were implanted with microinjection guide tubes aimed for the PnO. The PnO was microinjected with saline (control), hypocretin-1, the adenosine A(1) receptor agonist N(6)-p-sulfophenyladenosine (SPA), the hypocretin receptor-1 antagonist N-(2-Methyl-6-benzoxazolyl)-N''-1,5-naphthyridin-4-yl-urea (SB-334867), and hypocretin-1 plus SB-334867. As an index of antinociceptive behavior, the latency (in seconds) to paw withdrawal away from a thermal stimulus was measured following each microinjection. Compared to control, antinociception was significantly increased by hypocretin-1 and by SPA. SB-334867 increased nociceptive responsiveness, and administration of hypocretin-1 plus SB-334867 blocked the antinociception caused by hypocretin-1. These results suggest for the first time that hypocretin receptors in rat PnO modulate nociception.


CONCLUSIONS
Widely distributed and overlapping neural networks regulate states of sleep and pain. Specifying the brain regions and neurotransmitters through which pain and sleep interact is an essential step for developing adjunctive therapies that diminish pain without disrupting states of sleep and wakefulness.
Watson
Sarah L
SL
Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan 48109-5615, USA.
Watson
Christopher J
CJ
Baghdoyan
Helen A
HA
Lydic
Ralph
R
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D000375:Aging; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D006358:Hot Temperature; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008845:Microinjections; D009287:Naphthyridines; D009479:Neuropeptides / Q000378:metabolism*; D064446:Orexin Receptors; D000068797:Orexins; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism*; D010147:Pain Measurement; D011149:Pons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors / Q000378:metabolism; D012154:Reticular Formation / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D058907:Adenosine A1 Receptor Agonists; D001583:Benzoxazoles; C578627:Hcrtr1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; C109113:N(6)-(4-sulfophenyl)adenosine; D009287:Naphthyridines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043682:Receptor, Adenosine A1; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea; D000241:Adenosine