Thermal Nociception is Decreased by Hypocretin-1 and an Adenosine A1 Receptor Agonist Microinjected into the Pontine Reticular Formation of Sprague Dawley Rat

Abstract

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 -psulfophenyladenosine (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 s) 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. Keywords orexin; pain; sleepIn 2009, the American Pain Society 35 and the National Sleep Foundation 22 independently sponsored symposia on the topic of sleep and pain. The emerging appreciation of this relationship has been stimulated by evidence that pain states and sleep states are regulated by some of the same brain regions and neurotransmitters. Furthermore, preclinical 1 and human 14, 33, 36 studies make clear that sleep disruption causes hyperalgesia. These data are clinically relevant because opioids are a mainstay of pain management and opioids significantly disrupt sleep. 24 Opioid-induced sleep disruption and ensuing hyperalgesia may in turn increase opioid requirement. Adjunctive therapies that aid in pain management while reducing sleep Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Rats were anesthetized with isoflurane (induction = 3.5%; maintenance = 1.5-2.0%) and unilaterally implanted with an 8IC315GSPCXC model guide cannula (Plastics One, Roanoke, VA, USA) that was aimed to terminate above the stereotaxic coordinates of 8.4 mm posterior to bregma, 1.0 mm lateral to bregma, and 9.2 mm ventral to the skull surface. 30 When inserted into the guide cannula, the tip of the microinjector extended below the guide cannula into ...

Prevalence, clinical features and potential therapies for fibromyalgia in primary headaches

“…The total number of sleep hours are not dissimilar between FM and non-FM patients, while the quality of sleep seems to be the discriminating factor for FM in our headache series [18,26]. Clinical and preclinical data concur that sleep disruption causes hyperalgesia, and despite the widely distributed and overlapping neural networks that regulate states of sleep and pain, the brain mechanisms through which sleep and pain interact remain poorly understood [40,41]. A significant association of severe sleep disturbances and chronic headache [42,43] with central sensitization [44] has also been reported.…”

Hypocretin and GABA Interact in the Pontine Reticular Formation to Increase Wakefulness

“…33 This result demonstrates that the antinociceptive response is mediated by hypocretin receptors. Furthermore, blocking hypocretin receptors in the PnO with SB-334867 in the absence of exogenous hypocretin-1 increases nociceptive responsiveness to a thermal stimulus.…”

“…Furthermore, blocking hypocretin receptors in the PnO with SB-334867 in the absence of exogenous hypocretin-1 increases nociceptive responsiveness to a thermal stimulus. 33 This finding means that endogenous hypocretin-1 in rat PnO is antinociceptive. Microdialysis delivery of hypocretin-1 to rat PnO increases ACh release, 17 and ACh in the PnO of cat 34 and mouse 35 is antinociceptive.…”

“…In addition to its wakefulness-promoting actions, hypocretin-1 has antinociceptive effects, 56 which also can be evoked from the PnO. 33 Opioids are the most widely used drugs for the treatment of pain, and negative side effects include disruption of the sleep-wake cycle. 57 GABA levels in the PnO are decreased by opioids 28 and increased by hypocretin-1.…”

Effect of orexin-A (hypocretin-1) on hyperalgesic and cachectic manifestations of experimentally induced rheumatoid arthritis in rats

“…Also, it has been reported that thermal nociception is decreased by orexin-A microinjected into the pontine reticular formation of adult male Sprague-Dawley rats, and that this antinociception behavior was assessed by the latency (in seconds) to paw withdrawal away from thermal stimulus following each microinjection (Watson et al 2010). Furthermore, the findings of the current work supports previous reports that demonstrated orexin-A has analgesic properties, has a potential role in the modulation of nociceptive transmission, and may be applicable for treatment of pain (Bingham et al 2001 andSuyama et al 2004).…”