Skip to main content
SpringerLink
Log in

Noradrenergic Modulation of Itch Transmission in the Spinal Cord

  • Chapter
Pharmacology of Itch

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 226))

Abstract

Inhibition of both itching and scratching is important in the treatment of chronic pruritic diseases, because itching has a negative impact on quality of life and vigorous scratching worsens skin conditions. Pharmacological modulation of itch transmission in the dorsal horn is an effective way to inhibit both itching and scratching in pruritic diseases. Pruriceptive transmission in the spinal dorsal horn undergoes inhibitory modulation by the descending noradrenergic system. The noradrenergic inhibition is mediated by excitatory α1-adrenoceptors located on inhibitory interneurons and inhibitory α2-adrenoceptors located on central terminals of primary sensory neurons. The descending noradrenergic system and α-adrenoceptors in the dorsal horn are potential targets for antipruritic drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

GABA:

γ-Aminobutyric acid

mRNA:

Messenger ribonucleic acid

References

  • Akiyama T, Carstens MI, Carstens E (2011) Transmitters and pathways mediating inhibition of spinal itch-signaling neurons by scratching and other counterstimuli. PLoS One 6:e22665

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Akiyama T, Tominaga M, Carstens MI, Carstens EE (2012) Site-dependent and state-dependent inhibition of pruritogen-responsive spinal neurons by scratching. Eur J Neurosci 36:2311–2316

    Article  PubMed Central  PubMed  Google Scholar 

  • Andoh T, Gotoh Y, Kuraishi Y (2013) Milnacipran inhibits itch-related responses in mice through the enhancement of noradrenergic transmission in the spinal cord. J Pharmacol Sci 123:199–202

    Article  CAS  PubMed  Google Scholar 

  • Andrew D, Craig AD (2001) Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 4:72–77

    Article  CAS  PubMed  Google Scholar 

  • Baba H, Shimoji K, Yoshimura M (2000a) Norepinephrine facilitates inhibitory transmission in substantia gelatinosa of adult rat spinal cord (part 1): effects on axon terminals of GABAergic and glycinergic neurons. Anesthesiology 92:473–484

    Article  CAS  PubMed  Google Scholar 

  • Baba H, Goldstein PA, Okamoto M, Kohno T, Ataka T, Yoshimura M, Shimoji K (2000b) Norepinephrine facilitates inhibitory transmission in substantia gelatinosa of adult rat spinal cord (part 2): Effects on somatodendritic sites of GABAergic neurons. Anesthesiology 92:485–492

    Article  CAS  PubMed  Google Scholar 

  • Bajic D, Proudfit HK (1999) Projections of neurons in the periaqueductal gray to pontine and medullary catecholamine cell groups involved in the modulation of nociception. J Comp Neurol 405:359–379

    Article  CAS  PubMed  Google Scholar 

  • Bezerra MM, Lima V, Girao VC, Teixeira RC, Graca JR (2008) Antinociceptive activity of sildenafil and adrenergic agents in the writhing test in mice. Pharmacol Rep 60:339–344

    CAS  PubMed  Google Scholar 

  • Bromm B, Scharein E, Darsow U, Ring J (1995) Effects of menthol and cold on histamine-induced itch and skin reactions in man. Neurosci Lett 187:157–160

    Article  CAS  PubMed  Google Scholar 

  • Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP, Molinoff PB, Ruffolo RR Jr, Trendelenburg U (1994) International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol Rev 46:121–136

    CAS  PubMed  Google Scholar 

  • Carstens E (1997) Responses of rat spinal dorsal horn neurons to intracutaneous microinjection of histamine, capsaicin, and other irritants. J Neurophysiol 77:2499–2514

    CAS  PubMed  Google Scholar 

  • Cui M, Feng Y, McAdoo DJ, Willis WD (1999) Periaqueductal gray stimulation-induced inhibition of nociceptive dorsal horn neurons in rats is associated with the release of norepinephrine, serotonin, and amino acids. J Pharmacol Exp Ther 289:868–876

    CAS  PubMed  Google Scholar 

  • Davidson S, Zhang X, Khasabov SG, Simone DA, Giesler GJ Jr (2009) Relief of itch by scratching: state-dependent inhibition of primate spinothalamic tract neurons. Nat Neurosci 12:544–546

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gassner M, Ruscheweyh R, Sandkuhler J (2009) Direct excitation of spinal GABAergic interneurons by noradrenaline. Pain 145:204–210

    Article  CAS  PubMed  Google Scholar 

  • Gillen C, Haurand M, Kobelt DJ, Wnendt S (2000) Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol 362:116–121

    Article  CAS  PubMed  Google Scholar 

  • Gotoh Y, Andoh T, Kuraishi Y (2011a) Clonidine inhibits itch-related response through stimulation of α2-adrenoceptors in the spinal cord in mice. Eur J Pharmacol 650:215–219

    Article  CAS  PubMed  Google Scholar 

  • Gotoh Y, Andoh T, Kuraishi Y (2011b) Noradrenergic regulation of itch transmission in the spinal cord mediated by α-adrenoceptors. Neuropharmacology 61:825–831

    Article  CAS  PubMed  Google Scholar 

  • Gotoh Y, Omori Y, Andoh T, Kuraishi Y (2011c) Tonic inhibition of allergic itch signaling by the descending noradrenergic system in mice. J Pharmacol Sci 115:417–420

    Article  CAS  PubMed  Google Scholar 

  • Hagihira S, Senba E, Yoshida S, Tohyama M, Yoshiya I (1990) Fine structure of noradrenergic terminals and their synapses in the rat spinal dorsal horn: an immunohistochemical study. Brain Res 526:73–80

    Article  CAS  PubMed  Google Scholar 

  • Hagiwara K, Nojima H, Kuraishi Y (1999) Serotonin-induced biting of the hind paw is itch-related response in mice. Pain Res 14:53–59

    Article  Google Scholar 

  • Ide S, Minami M, Ishihara K, Uhl GR, Sora I, Ikeda K (2006) Mu opioid receptor-dependent and independent components in effects of tramadol. Neuropharmacology 51:651–658

    Article  CAS  PubMed  Google Scholar 

  • Jinks SL, Carstens E (2002) Responses of superficial dorsal horn neurons to intradermal serotonin and other irritants: comparison with scratching behavior. J Neurophysiol 87:1280–1289

    CAS  PubMed  Google Scholar 

  • Jones SL, Gebhart GF (1986) Characterization of coeruleospinal inhibition of the nociceptive tail-flick reflex in the rat: mediation by spinal alpha 2-adrenoceptors. Brain Res 364:315–330

    Article  CAS  PubMed  Google Scholar 

  • Kardon AP, Polgar E, Hachisuka J, Snyder LM, Cameron D, Savage S, Cai X, Karnup S, Fan CR, Hemenway GM, Bernard CS, Schwartz ES, Nagase H, Schwarzer C, Watanabe M, Furuta T, Kaneko T, Koerber HR, Todd AJ, Ross SE (2014) Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82:573–586

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kimura M, Obata H, Saito S (2012) Antihypersensitivity effects of tramadol hydrochloride in a rat model of postoperative pain. Anesth Analg 115:443–449

    Article  CAS  PubMed  Google Scholar 

  • Kitamura R, Andoh T, Mizoguchi S, Saito Y, Takahata H, Kuraishi Y (2014) Gabapentin inhibits bortezomib-induced mechanical allodynia through supraspinal action in mice. J Pharmacol Sci 124:502–510

    Article  CAS  PubMed  Google Scholar 

  • Koga K, Chen T, Li XY, Descalzi G, Ling J, Gu J, Zhuo M (2011) Glutamate acts as a neurotransmitter for gastrin releasing peptide-sensitive and insensitive itch-related synaptic transmission in mammalian spinal cord. Mol Pain 7:47

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kuraishi Y (2013) Potential new therapeutic targets for pathological pruritus. Biol Pharm Bull 36:1228–1234

    Article  CAS  PubMed  Google Scholar 

  • LaMotte RH, Shimada SG, Sikand P (2011) Mouse models of acute, chemical itch and pain in humans. Exp Dermatol 20:778–782

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Leibovici V, Magora F, Cohen S, Ingber A (2009) Effects of virtual reality immersion and audiovisual distraction techniques for patients with pruritus. Pain Res Manag 14:283–286

    PubMed Central  PubMed  Google Scholar 

  • Melzack R, Schecter B (1965) Itch and vibration. Science 147:1047–1048

    Article  CAS  PubMed  Google Scholar 

  • Mishra SK, Hoon MA (2013) The cells and circuitry for itch responses in mice. Science 340:968–971

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nicholson R, Dixon AK, Spanswick D, Lee K (2005) Noradrenergic receptor mRNA expression in adult rat superficial dorsal horn and dorsal root ganglion neurons. Neurosci Lett 380:316–321

    Article  CAS  PubMed  Google Scholar 

  • Omori Y, Andoh T, Shirakawa H, Ishida H, Hachiga T, Kuraishi Y (2009) Itch-related responses of dorsal horn neurons to cutaneous allergic stimulation in mice. Neuroreport 20:478–481

    Article  PubMed  Google Scholar 

  • Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A (2002) A TRP channel that senses cold stimuli and menthol. Cell 108:705–715

    Article  CAS  PubMed  Google Scholar 

  • Pertovaara A (2006) Noradrenergic pain modulation. Prog Neurobiol 80:53–83

    Article  CAS  PubMed  Google Scholar 

  • Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL (1992) Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 260:275–285

    CAS  PubMed  Google Scholar 

  • Rajaofetra N, Ridet JL, Poulat P, Marlier L, Sandillon F, Geffard M, Privat A (1992) Immunocytochemical mapping of noradrenergic projections to the rat spinal cord with an antiserum against noradrenaline. J Neurocytol 21:481–494

    Article  CAS  PubMed  Google Scholar 

  • Sandkühler J (1996) The organization and function of endogenous antinociceptive systems. Prog Neurobiol 50:49–81

    Article  PubMed  Google Scholar 

  • Sherrington CS (1906) Observations on the scratch-reflex in the spinal dog. J Physiol 34:1–50

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ständer S, Raap U, Weisshaar E, Schmelz M, Mettang T, Handwerker H, Luger TA (2011) Pathogenesis of pruritus. J Dtsch Dermatol Ges 9:456–463

    PubMed  Google Scholar 

  • Stone LS, Broberger C, Vulchanova L, Wilcox GL, Hökfelt T, Riedl MS, Elde R (1998) Differential distribution of α2A and α2C adrenergic receptor immunoreactivity in the rat spinal cord. J Neurosci 18:5928–5937

    CAS  PubMed  Google Scholar 

  • Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, Patapoutian A (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–829

    Article  CAS  PubMed  Google Scholar 

  • Sugiyama D, Hur SW, Pickering AE, Kase D, Kim SJ, Kawamata M, Imoto K, Furue H (2012) In vivo patch-clamp recording from locus coeruleus neurones in the rat brainstem. J Physiol 590:2225–2231

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF (2009) Cellular basis of itch sensation. Science 325:1531–1534

    Article  CAS  PubMed  Google Scholar 

  • Takasu K, Ono H, Tanabe M (2008) Gabapentin produces PKA-dependent pre-synaptic inhibition of GABAergic synaptic transmission in LC neurons following partial nerve injury in mice. J Neurochem 105:933–942

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi Y, Takasu K, Ono H, Tanabe M (2007) Pregabalin, S-(+)-3-isobutylgaba, activates the descending noradrenergic system to alleviate neuropathic pain in the mouse partial sciatic nerve ligation model. Neuropharmacology 53:842–853

    Article  CAS  PubMed  Google Scholar 

  • Tanabe M, Takasu K, Kasuya N, Shimizu S, Honda M, Ono H (2005) Role of descending noradrenergic system and spinal a2-adrenergic receptors in the effects of gabapentin on thermal and mechanical nociception after partial nerve injury in the mouse. Br J Pharmacol 144:703–714

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tohda C, Yamaguchi T, Kuraishi Y (1997) Intracisternal injection of opioids induces itch-associated response through μ-opioid receptors in mice. Jpn J Pharmacol 74:77–82

    Article  CAS  PubMed  Google Scholar 

  • Tsukumo Y, Matsumoto Y, Miura H, Yano H, Manabe H (2011) Gabapentin and pregabalin inhibit the itch-associated response induced by the repeated application of oxazolone in mice. J Pharmacol Sci 115:27–35

    Article  CAS  PubMed  Google Scholar 

  • Ueda M, Oyama T, Kuraishi Y, Akaike A, Satoh M (1995) Alpha2-adrenoceptor-mediated inhibition of capsaicin-evoked release of glutamate from rat spinal dorsal horn slices. Neurosci Lett 188:137–139

    Article  CAS  PubMed  Google Scholar 

  • Uhlen S, Porter AC, Neubig RR (1994) The novel alpha-2 adrenergic radioligand [3H]-MK912 is alpha-2C selective among human alpha-2A, alpha-2B and alpha-2C adrenoceptors. J Pharmacol Exp Ther 271:1558–1565

    CAS  PubMed  Google Scholar 

  • Ward L, Wright E, McMahon SB (1996) A comparison of the effects of noxious and innocuous counterstimuli on experimentally induced itch and pain. Pain 64:129–138

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi T, Maekawa T, Nishikawa Y, Nojima H, Kaneko M, Kawakita T, Miyamoto T, Kuraishi Y (2001) Characterization of itch-associated responses of NC mice with mite-induced chronic dermatitis. J Dermatol Sci 25:20–28

    Article  CAS  PubMed  Google Scholar 

  • Yeomans DC, Clark FM, Paice JA, Proudfit HK (1992) Antinociception induced by electrical stimulation of spinally projecting noradrenergic neurons in the A7 catecholamine cell group of the rat. Pain 48:449–461

    Article  CAS  PubMed  Google Scholar 

  • Yoshizumi M, Parker RA, Eisenach JC, Hayashida K (2012) Gabapentin inhibits γ-amino butyric acid release in the locus coeruleus but not in the spinal dorsal horn after peripheral nerve injury in rats. Anesthesiology 116:1347–1353

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Yasushi Kuraishi

Authors
  1. Yasushi Kuraishi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasushi Kuraishi .

Editor information

Editors and Affiliations

  1. Department of Pharmacology Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania, USA

    Alan Cowan

  2. Department of Dermatology, Temple University School of Medicine, Philadephia, Pennsylvania, USA

    Gil Yosipovitch

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Kuraishi, Y. (2015). Noradrenergic Modulation of Itch Transmission in the Spinal Cord. In: Cowan, A., Yosipovitch, G. (eds) Pharmacology of Itch. Handbook of Experimental Pharmacology, vol 226. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-44605-8_12

Download citation

Publish with us

Policies and ethics

Search

Navigation