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

Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan 48109-5615, USA.
The journal of pain: official journal of the American Pain Society (Impact Factor: 4.01). 12/2009; 11(6):535-44. DOI: 10.1016/j.jpain.2009.09.010
Source: PubMed


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. PERSPECTIVE: 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.

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Available from: Christopher J Watson, Apr 02, 2014
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    • "There are several evidence indicating the involvement of orexin-A in modulation of nociceptive behavior (Yamamoto et al., 2003; Holland et al., 2005; Y.K. et al., 2005). For example, it has been reported that orexin-A microinjection could induce analgesia in different parts of the brain via affecting OX1R (Watson et al., 2010; Azhdari Zarmehri et al., 2011). Also, studies have demonstrated that OX1R is involved in the development of morphine induced analgesia and tolerance (Ranjbar-Slamloo et al., 2012; Erami et al., 2012; Azhdari-Zarmehri et al., 2013). "
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    ABSTRACT: Long-term administration of opiates leads to development of tolerance to analgesic effects. This in turn compromise clinical use of these drugs for pain management. Although extensive studies have been conducted, the involved cellular mechanisms are still poorly understood. The nucleus locus coeruleus (LC), which is a dense homogenous cluster of noradrenergic neurons in brainstem, has been reported to be involved in mediating opiate effects including analgesia and tolerance. LC neurons express a high density of opioid receptors. On the other hand, orexinergic neurons send widespread projections to the LC region. Among the two types of orexin receptors (OX1R and OX2R), OX1R is highly expressed in LC neurons. It has been shown that orexin-A is involved in modulation of nociceptive behavior. Also, previous studies have demonstrated the involvement of OX1R in the development of morphine induced analgesia and tolerance. In the present study, the involvement of OX1R in development of met-enkephalin (ME) analgesic tolerance was investigated in LC nucleus. The tail flick test was used to evaluate the analgesic effect of intra-LC microinjection of ME in male Wistar rats (250-300g). Analgesic responses were reported as the percentage of maximum possible effect (% of MPE). Also, SB-334867 was used as a selective OX1R antagonist. Results indicate that intra-LC microinjection of ME (5μg/100nL) results in development of analgesic tolerance in 3days. Also, OX1R antagonism in LC nucleus significantly prevents the analgesic effect of intra-LC met-enkephalin microinjection. It appears that the analgesic effect of ME in LC neurons is mediated by orexinergic system. Copyright © 2015. Published by Elsevier Inc.
    Pharmacology Biochemistry and Behavior 07/2015; 136. DOI:10.1016/j.pbb.2015.07.010 · 2.78 Impact Factor
    • "The present study focused on the pontine brain stem because adenosinergic transmission in the pontine reticular formation contributes to the regulation of sleep (Baghdoyan and Lydic, 2012; Gettys et al., 2013) and nociception (Kshatri et al., 1998; Tanase et al., 2002; Wang et al., 2009; Watson et al., 2010). Chronic sleep restriction facilitates the development of obesity (Spiegel et al., 1999; Morselli et al., 2010), increases leptin as a modulator of pro-inflammatory cytokines (reviewed in (Hayes et al., 2011), and— even in healthy volunteers—increases pain (Roehrs et al., 2006; Haack et al., 2007). "
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    ABSTRACT: Human obesity is associated with increased leptin levels and pain, but the specific brain regions and neurochemical mechanisms underlying this association remain poorly understood. This study used adult male C57BL/6J (B6, n = 14) mice and leptin-deficient, obese B6.Cg-Lep(ob)/J (obese, n = 10) mice to evaluate the hypothesis that nociception is altered by systemic leptin levels and by adenosine A1 receptors in the pontine reticular formation. Nociception was quantified as paw withdrawal latency (PWL) in s after onset of a thermal stimulus. PWL wasconverted topercent maximum possible effect (%MPE). After obtaining baseline PWL measures, the pontine reticular formation was microinjected with saline (control), three concentrations of the adenosine A1 receptor agonist N(6)-p-sulfophenyladenosine (SPA), or super-active mouse leptin receptor antagonist (SMLA) followed by SPA 15 min later, and PWL was again quantified. In obese, leptin-deficient mice, nociception was quantified before and during leptin replacement via subcutaneous osmotic pumps. SPA was administered into the pontine reticular formation of leptin-replaced mice and PWL testing was repeated. During baseline (before vehicle or SPA administration), PWL was significantly (p = 0.0013) lower in leptin-replaced obese mice than in B6 mice. Microinjecting SPA into the pontine reticular formation of B6 mice caused a significant (p = 0.0003) concentration-dependent increase in%MPE. SPA also significantly (p < 0.05) increased%MPE in B6 mice and in leptin-replaced obese mice, but not in leptin-deficient obese mice. Microinjection of the mouse super-active leptin antagonist (SMLA) into the pontine reticular formation before SPA did not alter PWL. The results show for the first time that pontine reticular formation administration of the adenosine A1 receptor agonist SPA produced antinociception only in the presence of systemic leptin. The concentration-response data support the interpretation that adenosine A1 receptors localized to the pontine reticular formation significantly alter nociception.
    Neuroscience 06/2014; 275. DOI:10.1016/j.neuroscience.2014.06.025 · 3.36 Impact Factor
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    • "In all of those models, the orexin-induced analgesic effects were suppressed by the OX1 receptor antagonist SB-334867 but not by naloxone, an opioid receptor inverse agonist, suggesting that regulation of nociception by orexin is independent of the opiate system (Figure 2). In addition to the direct projection of orexin neurons to the spinal cord (van den Pol, 1999), orexin signalling in the posterior hypothalamic area (Bartsch et al., 2004), the pontine reticular nucleus, oral part (Watson et al., 2010), and periaqueductal gray matter have been shown to be important for its antinociceptive effects. Moreover, orexin plays a significant role in the regulation of stress-induced analgesia (SIA), coordinating with the nociceptin/orphanin FQ systems (Xie et al., 2008; Gerashchenko et al., 2011). "
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    ABSTRACT: The hypocretins (Hcrts), also known as orexins, are two peptides derived from a single precursor produced in the posterior lateral hypothalamus. Over the past decade, the hypocretin system has been associated to numerous physiological functions, including sleep/arousal, energy homeostasis, endocrine, visceral functions and pathological states, such as narcolepsy and drug abuse. Here we will review the discovery of Hcrt/orexins and their receptors and propose a hypothesis as to how the Hcrt system orchestrates these myriad physiological functions.
    British Journal of Pharmacology 09/2013; 171(2). DOI:10.1111/bph.12415 · 4.84 Impact Factor
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