Lateral Hypothalamic Stimulation Reduces Hyperalgesia Through Spinally Descending Orexin-A Neurons in Neuropathic Pain

Abstract

No evidence to date shows that lateral hypothalamic (LH) stimulation produces orexin-A-mediated antinociception in the spinal cord dorsal horn (SCDH) in a model of neuropathic pain. We conducted experiments to examine the effect of orexin-A-mediated LH stimulation in female rats with chronic constriction injury (CCI) on thermal hyperalgesia. Rats receiving carbachol into the LH demonstrated antinociception on both the left CCI and right nonligated paws (p < .05). Rats were given carbachol in the LH followed by intrathecal injection of the orexin-1 (OX₁) receptor antagonist SB-334867, which blocked LH-induced antinociception compared with control groups (p < .05) in the left paw, but not in the right paw. These findings support the hypothesis that LH stimulation produces antinociception in rats with thermal hyperalgesia from neuropathic pain via an orexin-A connection between the LH and the SCDH. Identification of this pathway may lead to studies using orexins to manage clinical pain.

Keywords

neuropathic pain orexin lateral hypothalamus

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References

Acuna-Goycolea

van den Pol

A. N.

(2009). Neuroendocrine proopiomelanocortin neurons are excited by hypocretin/orexin. Journal of Neuroscience, 29, 1503-1513. doi:10.1523/JNEUROSCI.5147-08.2009

Antal

Petko

Polgar

Heizmann

Storm-Mathisen

(1996). Direct evidence of an extensive GABAergic innervation of the spinal dorsal horn by fibres descending from the rostral ventromedial medulla. Neuroscience, 73, 509-518.

Bardoni

Takazawa

Tong

Choudhury

Scherrer

MacDermott

A. B.

(2013). Pre and postsynaptic inhibitory control in the spinal cord dorsal horn. Annals of the New York Academy of Sciences, 1279, 90-96.

Bartsch

Levy

Knight

Goadsby

(2004). Differential modulation of the nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain, 109, 367-378.

Bennett

G. J.

Xie

(1988). A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain, 33, 87-107.

Berger

Dukes

E. M.

Oster

(2004). Clinical characteristics and economic costs of patients with painful neuropathic disorders. Journal of Pain, 5, 143-149. doi:10.1016/j.jpain.2003.12.004

Biagioni

A. F.

de Freitas

R. L.

da Silva

J. A.

de Oliveira

R. C.

de Oliveira

Alves

V. M.

Coimbra

N. C.

(2013). Serotonergic neural links from the dorsal raphe nucleus modulate defensive behaviours organised by the dorsomedial hypothalamus and the elaboration of fear-induced antinociception via locus coeruleus pathways. Neuropharmacology, 67, 379-394.

Cheng

J. K.

Chou

R. C.

Hwang

L. L.

Chiou

L. C.

(2003). Antiallodynic effects of intrathecal orexins in a rat model of postoperative pain. Journal of Pharmacology and Experimental Therapeutics, 307, 1067-1071. doi:10.1124/jpet.103.056663

Clark

F. M.

Proudfit

H. K.

(1991). The projection of noradrenergic neurons in the A7 catecholamine cell group to the spinal cord in the rat demonstrated by anterograde tracing combined with immunocytochemistry. Brain Research, 547, 279-288.

10.

Cluderay

Harrison

Hervieu

(2002). Protein distribution of the orexin-2 receptor in the rat central nervous system. Regulatory Peptides, 104, 131-144.

11.

Cocito

Paolasso

Pazzaglia

Tavella

Poglio

Ciaramitaro

. . . Padua

(2006). Pain affects the quality of life of neuropathic patients. Neurological Sciences, 27, 155-160. doi:10.1007/s10072-006-0660-5

12.

Currow

D. C.

Clark

Kamal

Collier

Agar

M. R.

Lovell

M. R.

. . . Ritchie

(2015). The population burden of chronic symptoms that substantially predate the diagnosis of a life-limiting illness. Journal of Palliative Medicine, 18, 480-485. doi:10.1089/jpm.2014.0444

13.

Dafny

Dong

Prieto-Gomez

Reyes-Vazquez

Stanford

Qiao

(1996). Lateral hypothalamus: Site involved in pain modulation. Neuroscience, 70, 449-460.

14.

Daousi

Benbow

S. J.

Woodward

MacFarlane

I. A.

(2006). The natural history of chronic painful peripheral neuropathy in a community diabetes population. Diabetic Medicine, 23, 1021-1024.

15.

Doroshenko

Renaud

(2009). Acid-sensitive TASK-like K+ conductances contribute to resting membrane potential and to orexin-induced membrane depolarization in rat thalamic paraventricular nucleus neurons. Neuroscience, 158, 1560-1570.

16.

Fillingim

R. B.

King

C. D.

Ribeiro-Dasilva

M. C.

Rahim-Williams

Riley

J. L.

III . (2009). Sex, gender, and pain: A review of recent clinical and experimental findings. Journal of Pain, 10, 447-485. doi:10.1016/j.jpain.2008.12.001

17.

Gilron

Baron

Jensen

(2015). Neuropathic pain: Principles of diagnosis and treatment. Mayo Clinic Proceedings, 90, 532-545.

18.

Gotter

A. L.

Webber

A. L.

Coleman

P. J.

Renger

J. J.

Winrow

C. J.

(2012). International union of basic and clinical pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology. Pharmacological Reviews, 64, 389-420. doi:10.1124/pr.111.005546

19.

Grossman

S. P.

Stumpf

W. E.

(1969). Intracranial drug implants: An autoradiographic analysis of diffusion. Science, 166, 1410-1412.

20.

Guan

Wang

Hori

Takenoya

Kageyama

Shioda

(2004). Ultrastructure of orexin-1 receptor immunoreactivities in the spinal cord dorsal horn. Peptides, 25, 1307-1311.

21.

Hancock

(1976). Cells of origin of hypothalamo-spinal projections in the rat. Neuroscience Letters, 3, 179-184.

22.

Holden

J. E.

Farah

E. N.

Jeong

(2005). Stimulation of the lateral hypothalamus produces antinociception mediated by 5-HT_1A, 5-HT_1B and 5HT₃ receptors in the rat spinal cord dorsal horn. Neuroscience, 135, 1255-1268.

23.

Holden

J. E.

Van Poppel

A. Y.

Thomas

(2002). Antinociception from lateral hypothalamic stimulation may be mediated by NK 1 receptors in the A7 catecholamine cell group in rat. Brain Research, 953, 195-204.

24.

Holden

J. E.

Wang

Moes

J. R.

Wagner

Maduko

Jeong

(2014). Differences in carbachol dose, pain condition, and sex following lateral hypothalamic stimulation. Neuroscience, 270, 226-235.

25.

Holland

P. R.

Akerman

Goadsby

P. J.

(2005). Orexin 1 receptor activation attenuates neurogenic dural vasodilation in an animal model of trigeminovascular nociception. Journal of Pharmacology and Experimental Therapeutics, 315, 1380-1385.

26.

Ishibashi

Gumenchuk

Leonard

C. S.

(2012, October). Orexin-A enhances a slow afterhyperpolarization (sAHP) and slows steady firing in serotonergic dorsal raphe (DR) neurons. Poster session presented at the meeting of the Society for Neuroscience, New Orleans, LA.

27.

Jeong

Holden

J. E.

(2009a). Lateral hypothalamic-induced alpha-adrenoceptor modulation occurs in a model of inflammatory pain in rats. Biological Research for Nursing, 10, 331-339. doi:10.1177/1099800408325053

28.

Jeong

Holden

J. E.

(2009b). The role of spinal orexin-1 receptors in posterior hypothalamic modulation of neuropathic pain. Neuroscience, 159, 1414-1421.

29.

Jeong

Moes

J. R.

Wagner

Holden

J. E.

(2012). The posterior hypothalamus exerts opposing effects on nociception via the A7 catecholamine cell group in rats. Neuroscience, 227, 144-153.

30.

Kajiyama

Kawamoto

Shiraishi

Gaus

Matsunaga

Suyama

Yuge

(2005). Spinal orexin-1 receptors mediate anti-hyperalgesic effects of intrathecally-administered orexins in diabetic neuropathic pain model rats. Brain Research, 1044, 76-86.

31.

Kim

K. J.

Chung

J. M.

(1997). Comparison of three rodent neuropathic pain models. Experimental Brain Research, 113, 200-206.

32.

Leonard

Kukkonen

(2014). Orexin/hypocretin receptor signalling: A functional perspective. British Journal of Pharmacology, 171, 294-313.

33.

Lum

J. T.

Nguyen

Felpel

L. P.

(1984). Drug distribution in solid tissue of the brain following chronic local perfusion utilizing implanted osmotic minipumps. Journal of Pharmacological Methods, 12, 141-147.

34.

Martin

J. R.

Knuepfer

M. M.

Westfall

T. C.

(1991). Hemodynamic effects of posterior hypothalamic injection of neuropeptide Y in awake rats. American Journal of Physiology, 261(3, Pt. 2), H814-H824.

35.

Mogil

J. S.

Chanda

M. L.

(2005). The case for the inclusion of female subjects in basic science studies of pain. Pain, 117, 1-5.

36.

Myers

Hoch

(1978). 14 C-dopamine microinjected into the brain-stem of the rat: Dispersion kinetics, site content and functional dose. Brain Research Bulletin, 3, 601-609.

37.

Nicholson

(1985). Diffusion from an injected volume of a substance in brain tissue with arbitrary volume fraction and tortuosity. Brain Research, 333, 325-329.

38.

Paxinos

Watson

(2009). The rat brain in stereotaxic coordinates. San Diego, CA: Academic Press.

39.

Peyron

Tighe

D. K.

van den Pol

A. N.

de Lecea

Heller

H. C.

Sutcliffe

J. G.

Kilduff

T. S.

(1998). Neurons containing hypocretin (orexin) project to multiple neuronal systems. Journal of Neuroscience, 18, 9996-10015.

40.

Sakai

Swartz

B. E.

Woody

(1979). Controlled micro release of pharmacological agents: Measurements of volume ejected in vitro through fine tipped glass microelectrodes by pressure. Neuropharmacology, 18, 209-213.

41.

Sakurai

Amemiya

Ishii

Matsuzaki

Chemelli

R. M.

Tanaka

. . . Yanagisawa

(1998). Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 92, 573-585.

42.

Son

B. C.

Kim

D. R.

Kim

H. S.

Lee

S. W.

(2014). Simultaneous trial of deep brain and motor cortex stimulation in chronic intractable neuropathic pain. Stereotactic and Functional Neurosurgery, 92, 218-226. doi:10.1159/000362933

43.

Suyama

Kawamoto

Shiraishi

Gaus

Kajiyama

Yuge

(2004). Analgesic effect of intrathecal administration of orexin on neuropathic pain in rats. In Vivo, 18, 119-123.

44.

van den Pol

A. N.

Gao

X. B.

Obrietan

Kilduff

T. S.

Belousov

A. B.

(1998). Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. Journal of Neuroscience, 18, 7962-7971.

45.

Werhagen

Hultling

Molander

(2007). The prevalence of neuropathic pain after non-traumatic spinal cord lesion. Spinal Cord, 45, 609-615.

46.

Willis

Westlund

(1997). Neuroanatomy of the pain system and of the pathways that modulate pain. Journal of Clinical Neurophysiology, 14, 2-31.

47.

World Health Organization. (2006). Neurological disorders: Public health challenges. Geneva, Switzerland: Author.

48.

Yamamoto

Saito

Shono

Aoe

Chiba

(2003). Anti-mechanical allodynic effect of intrathecal and intracerebroventricular injection of orexin-A in the rat neuropathic pain model. Neuroscience Letters, 347, 183-186.

49.

Yeomans

D. C.

Proudfit

H. K.

(1994). Characterization of the foot withdrawal response to noxious radiant heat in the rat. Pain, 59, 85-94.