Elsevier

Neuroscience

Volume 159, Issue 4, 10 April 2009, Pages 1414-1421
Neuroscience

Pain Mechanism
The role of spinal orexin-1 receptors in posterior hypothalamic modulation of neuropathic pain

https://doi.org/10.1016/j.neuroscience.2009.02.006Get rights and content

Abstract

The posterior hypothalamus (PH) is known to reduce nociceptive pain, but the effect of PH stimulation on neuropathic pain is not known. Because neurons containing the neurotransmitter orexin-A are located in the PH in some strains of rat and intrathecal injection of orexin-A produces antinociception in a neuropathic pain model, we hypothesized that orexin-A from neurons in the PH modifies nociception in the spinal cord dorsal horn. To test this hypothesis, the cholinergic agonist carbachol or normal saline was microinjected into the PH of lightly anesthetized female Sprague–Dawley rats with chronic constriction injury (CCI) and foot withdrawal latencies (FWL) were measured. Carbachol-induced PH stimulation produced dose dependent antinociception as shown by significantly increased FWL compared to saline controls. To investigate the role of orexin-A in PH-induced antinociception, the orexin-1 receptor antagonist SB-334867 or dimethyl sulfoxide (DMSO) for control, was given intrathecally following carbachol-induced PH stimulation. SB-334867 decreased FWL compared to DMSO controls. These data are suggestive that stimulating the PH produces antinociception in a neuropathic pain model and that the antinociceptive effect is mediated in part by orexin-1 receptors in the spinal cord dorsal horn.

Section snippets

Experimental procedures

The Institutional Animal Care Committee at the University of Illinois at Chicago approved the experimental protocols used in this study. The experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 90–23). All efforts were made to minimize animal suffering, reduce the numbers of animals used, and use alternatives to in vivo experiments.

Results

Of the 89 rats used, 19 were excluded. Three rats showed self-mutilation; five rats did not exhibit neuropathic behaviors on the left affected foot; and 11 rats showed misplacement of either intracranial, intrathecal, or both cannulae.

Discussion

In the present study, we demonstrated that carbachol-induced PH stimulation produced a robust antinociceptive response in female rats with CCI compared to rats given saline in the PH. This antinociceptive response was mediated by cholinergic receptors in the PH, and blocked by intrathecal administration of the OX1R antagonist, SB-334867. While these findings are novel and are suggestive of a direct projection from orexin-containing neurons in the PH to the dorsal horn, we cannot say with

Conclusion

In summary, PH stimulation with carbachol decreased CCI neuropathic pain as demonstrated by increased foot withdrawal latencies. Pretreatment with atropine sulfate blocked PH-induced antinociception. Intrathecal application of an OX1R antagonist significantly decreased foot withdrawal latencies compared to DMSO controls, while the OX1R antagonist given alone had no effect in neuropathic pain. These findings are suggestive that cholinergic muscarinic receptors mediate activation of PH neurons

Acknowledgments

This work was supported by Midwest Nursing Research Society/American Nurses Foundation grant and USPHS grant HHS NR04778 from the National Institute of Nursing Research at the National Institutes of Health.

References (77)

  • D.J. Cutler et al.

    Differential distribution of orexin-A and orexin-B immunoreactivity in the rat brain and spinal cord

    Peptides

    (1999)
  • Y. Date et al.

    Distribution of orexin-A and orexin-B (hypocretins) in the rat spinal cord

    Neurosci Lett

    (2000)
  • A.A. Fleming et al.

    Thyrotropin-releasing hormone- and GABA-like immunoreactivity coexist in neurons in the dorsal horn of the rat spinal cord

    Brain Res

    (1994)
  • J.L. Guan et al.

    Ultrastructure of orexin-1 receptor immunoreactivities in the spinal cord dorsal horn

    Peptides

    (2004)
  • G.J. Hervieu et al.

    Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord

    Neuroscience

    (2001)
  • J.E. Holden et al.

    Stimulation of the lateral hypothalamus produces antinociception mediated by 5-HT1A, 5-HT1B and 5-HT3 receptors in the rat spinal cord dorsal horn

    Neuroscience

    (2005)
  • J.E. Holden et al.

    Microinjection of carbachol in the lateral hypothalamus produces opposing actions on nociception mediated by alpha(1)-and alpha(2)-adrenoceptors

    Brain Res

    (2001)
  • J.E. Holden et al.

    Microinjection of morphine in the A7 catecholamine cell group produces opposing effects on nociception that are mediated by alpha1- and alpha2-adrenoceptors

    Neuroscience

    (1999)
  • J.E. Holden et al.

    Antinociception from lateral hypothalamic stimulation may be mediated by NK(1) receptors in the A7 catecholamine cell group in rat

    Brain Res

    (2002)
  • V. Jevtovic-Todorovic et al.

    Clonidine potentiates the neuropathic pain-relieving action of MK-801 while preventing its neurotoxic and hyperactivity side effects

    Brain Res

    (1998)
  • K.C. Kajander et al.

    Fos-like immunoreactivity increases in the lumbar spinal cord following a chronic constriction injury to the sciatic nerve of rat

    Neurosci Lett

    (1996)
  • S. Kajiyama et al.

    Spinal orexin-1 receptors mediate anti-hyperalgesic effects of intrathecally-administered orexins in diabetic neuropathic pain model rats

    Brain Res

    (2005)
  • G.A. Kerchner et al.

    Direct presynaptic regulation of GABA/glycine release by kainate receptors in the dorsal horn: an ionotropic mechanism

    Neuron

    (2001)
  • J.G. Klamt et al.

    Antinociception and behavioral changes induced by carbachol microinjected into identified sites of the rat brain

    Brain Res

    (1991)
  • T. Kodama et al.

    Arousal effects of orexin-A correlate with GLU release from the locus coeruleus in rats

    Peptides

    (2002)
  • J.W. Leiphart et al.

    Decreased spinal alpha2a- and alpha2c-adrenergic receptor subtype mRNA in a rat model of neuropathic pain

    Neurosci Lett

    (2003)
  • B.H. Manning et al.

    Morphine analgesia in the formalin test: reversal by microinjection of quaternary naloxone into the posterior hypothalamic area or periaqueductal gray

    Behav Brain Res

    (1998)
  • J. Mao et al.

    Increases in protein kinase C gamma immunoreactivity in the spinal cord dorsal horn of rats with painful mononeuropathy

    Neurosci Lett

    (1995)
  • M.J. Millan

    The induction of pain: an integrative review

    Prog Neurobiol

    (1999)
  • M.J. Millan et al.

    Evidence for a role of the ventro-medial posterior hypothalamus in nociceptive processes in the rat

    Pharmacol Biochem Behav

    (1983)
  • J.S. Mogil et al.

    The case for the inclusion of female subjects in basic science studies of pain

    Pain

    (2005)
  • T. Nambu et al.

    Distribution of orexin neurons in the adult rat brain

    Brain Res

    (1999)
  • K. Ren et al.

    Nerve growth factor alleviates a painful peripheral neuropathy in rats

    Brain Res

    (1995)
  • D.L. Rhodes et al.

    Analgesia from rostral brain stem stimulation in the rat

    Brain Res

    (1978)
  • L.S. Ro et al.

    Territorial and extra-territorial distribution of Fos protein in the lumbar spinal dorsal horn neurons in rats with chronic constriction nerve injuries

    Brain Res

    (2004)
  • T. Sakurai et al.

    Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior

    Cell

    (1998)
  • H. Tsuruhara et al.

    Glial and potassium responses to an afferent volley: suppression by enkephalin in the rat spinal cord in vitro

    Neurosci Lett

    (1987)
  • R. Wagner et al.

    Anti-inflammatory interleukin-10 therapy in CCI neuropathy decreases thermal hyperalgesia, macrophage recruitment, and endoneurial TNF-alpha expression

    Pain

    (1998)
  • Cited by (34)

    • Effects of intrathecal administration of orexin-1 receptor antagonist on antinociceptive responses induced by chemical stimulation of lateral hypothalamus in an animal model of tonic nociception

      2018, Neuropeptides
      Citation Excerpt :

      Moreover, they reported that intrathecal injection of SB-334867 alone had no effect in the formalin test or in the hot plate test. Additionally, Jeong and Holden (2009) have demonstrated the role of spinal orexin-1 receptors in posterior hypothalamus (PH) in modulation of neuropathic pain. However, considering the volume of the carbachol administered, the activation of this area (PH) was lesser than that in the LH.

    • A review of the role of orexin system in pain modulation

      2017, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      Moreover, in another study the effect of orexin-A on high K+-induced [Ca2+]i increase was attributed to the inhibition of Ca2+ influx through L-type Ca2+ channel in dorsal root ganglion (DRG) neurons of rat segmental spinal nerve ligation (SNL) model, which may have important implications for nociceptive modulation and pain, so that, nifedipine and lidocaine strongly inhibited on the high K+-induced depolarization [Ca2+]i increase in sham and SNL groups, while orexine-A inhibited on the high K+-induced depolarization [Ca2+]i increase in DRG neurons [26]. According to another study, the antinociception effect of orexin-A in a neuropathic pain model in rat (chronic constriction injury) through stimulating the posterior hypothalamus by cholinergic agonist carbachol microinjection is mediated partly via orexin receptor type-1 in the spinal cord dorsal horn [27]. Stress-induced analgesia is a key component of the defensive behavioral reaction to prepare for fight or flight [28].

    • Modulation of nociception by medial pre-optic area orexin a receptors and its relation with morphine in male rats

      2016, Brain Research Bulletin
      Citation Excerpt :

      Also, according to the in vivo and in vitro electrophysiological studies, orexin A and orexin B have an essential role in spinal sensory transmission, respectively (Grudt et al., 2002; Peng et al., 2008). Based on a large body of literature on behavioral and pharmacological aspects of orexin A and B administration, supporting these electrophysiological evidences, it has been deduced that the intrathecal administration of orexin A and, to a lesser extent, orexin B inhibits withdrawal response and spontaneous nociceptive behavior in acute, inflammatory, chemical, neuropathic, and postsurgical models of pain (Bingham et al., 2001; Cheng et al., 2003; Jeong and Holden, 2009; Kajiyama et al., 2005; Mobarakeh et al., 2005a; Sakurai et al., 1998; Yamamoto et al., 2002, 2003). The anti-nociceptive actions of orexins was blocked via intrathecally administered SB-334867, once again exhibiting that pain modulation can be mediated through OX1 receptors (Gotter et al., 2012).

    View all citing articles on Scopus
    View full text