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The Journal of Physiological Sciences

, Volume 67, Issue 3, pp 431–438 | Cite as

Noradrenergic inhibition of spinal hyperexcitation elicited by cutaneous cold stimuli in rats with oxaliplatin-induced allodynia: electrophysiological and behavioral assessments

Short Communication

Abstract

We investigated the spinal action of noradrenaline on cold-elicited hyperexcitation detected in dorsal horn neurons of rats with allodynia induced by an oxaliplatin (6 mg/kg, i.p.) injection. In vivo extracellular recordings from the spinal dorsal horn showed that wide dynamic range neurons responded to cutaneous acetone (10 μl) stimulation in normal rats, and cold-elicited firings in oxaliplatin-administered rats were increased with a longer duration, correlated with behavioral responses. These responses were significantly attenuated by spinal administration (50 μM) of noradrenaline or its agonists, clonidine (α2), phenylephrine (α1) and isoprenaline (β), in descending order of efficacy. Thus, the inhibitory effect of noradrenaline on spinal oxaliplatin-induced cold hyperexcitation is mediated mainly by activation of α2- and/or α1-adrenoceptors.

Keywords

Noradrenaline Oxaliplatin Cold allodynia Spinal cord Wide dynamic range neurons In vivo extracellular recording 

Notes

Acknowledgements

We would like to thank Dr. Kazuhiko Seki and Ms. Ayumi Nakamura for their helpful advice on data analysis and technical support. This work was supported by grants from the programs Grants-in-Aid for Scientific Research (H.F.) from the Ministry of Education, Science, Sports and Culture of Japan, by a grant from the National Research Foundation of Korea (S.K.K) funded by the Korea Government (NRF-2013R1A1A1012403), and by a Grant (S.K.K.) from the Korea Institute of Oriental Medicine (C15012).

Compliance with ethical standards

Conflicts of interest

The authors declare no conflict of interest.

Supplementary material

12576_2016_505_MOESM1_ESM.pdf (17 kb)
Supplementary Fig. 1. Firing rates of spinal WDR neurons during mechanical stimuli and behavioral signs of mechanical hypersensitivity. (A–C) Increased firings caused by light touch (brushing with camel hair) (A), press (pressing with the tip of brush) (B), and pinch (pinching with forceps) (C), were observed in oxaliplatin injected model (N = 20 for each group). ***p < 0.001, *p < 0.05, by unpaired t-test. (D–E) von Frey hair test showed that no change in mechanical sensitivity before and after vehicle control injection was observed (D), whereas mechanical hypersensitivity was developed following oxaliplatin injection (E). N = 7 for control group and N = 8 for oxaliplatin group. **p < 0.01, by paired t-test. (PDF 17 kb)
12576_2016_505_MOESM2_ESM.pdf (18 kb)
Supplementary Fig. 2. Mechanical response durations in control and oxaliplatin injected rats. Total response duration of spinal WDR neurons to cold acetone stimulation, but not to press or pinch stimulation, was augmented by oxaliplatin (A). High frequency response of neuronal firing was elicited by pinch (B) or press (C) within stimulation duration (3 s) in oxaliplatin-administered rats. No or little significant difference in firing rates after pinch (B) or press (C) stimulation was observed between control and oxaliplatin groups. N = 17 for control group and N = 21 for oxaliplatin group. *p < 0.05, **p < 0.01, ***p < 0.001, by unpaired t-test. (PDF 17 kb)

References

  1. 1.
    André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A, Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351CrossRefGoogle Scholar
  2. 2.
    Meyerhardt JA, Mayer RJ (2005) Systemic therapy for colorectal cancer. N Engl J Med 352:476–487CrossRefPubMedGoogle Scholar
  3. 3.
    Wolf S, Barton D, Kottschade L, Grothey A, Loprinzi C (2008) Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer 44:1507–1515CrossRefPubMedGoogle Scholar
  4. 4.
    Millan MJ (2002) Descending control of pain. Prog Neurobiol 66:355–474CrossRefPubMedGoogle Scholar
  5. 5.
    Sonohata M, Furue H, Katafuchi T, Yasaka T, Doi A, Kumamoto E, Yoshimura M (2004) Actions of noradrenaline on substantia gelatinosa neurones in the rat spinal cord revealed by in vivo patch recording. J Physiol 555:515–526CrossRefPubMedGoogle Scholar
  6. 6.
    Pertovaara A, Almeida A (2006) Descending inhibitory systems. In: Cervero F, Jensen TS (eds) Handbook of clinical neurology, vol 81. Elsevier, AmsterdamGoogle Scholar
  7. 7.
    Yoshimura M, Furue H (2006) Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord. J Pharmacol Sci 101:107–117CrossRefPubMedGoogle Scholar
  8. 8.
    Todd AJ (2010) Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci 11:823–836CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Yaksh TL (1985) Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacol Biochem Behav 22:845–858CrossRefPubMedGoogle Scholar
  10. 10.
    Omote K, Kawamata T, Kawamata M, Namiki A (1998) Formalin-induced nociception activates a monoaminergic descending inhibitory system. Brain Res 814:194–198CrossRefPubMedGoogle Scholar
  11. 11.
    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 53:842–853CrossRefPubMedGoogle Scholar
  12. 12.
    Nakajima K, Obata H, Iriuchijima N, Saito S (2012) An increase in spinal cord noradrenaline is a major contributor to the antihyperalgesic effect of antidepressants after peripheral nerve injury in the rat. Pain 153:990–997CrossRefPubMedGoogle Scholar
  13. 13.
    Lim BS, Moon HJ, Li DX, Gil M, Min JK, Lee G, Bae H, Kim SK, Min BI (2013) Effect of bee venom acupuncture on oxaliplatin-induced cold allodynia in rats. Evid Based Complement Alternat Med 2013:1–8Google Scholar
  14. 14.
    Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110CrossRefPubMedGoogle Scholar
  15. 15.
    Lee JH, Li DX, Yoon H, Go D, Quan FS, Min BI, Kim SK (2014) Serotonergic mechanism of the relieving effect of bee venom acupuncture on oxaliplatin-induced neuropathic cold allodynia in rats. BMC Complement Altern Med 14:471CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Choi Y, Yoon YW, Na HS, Kim SH, Chung JM (1994) Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain 59:369–376CrossRefPubMedGoogle Scholar
  17. 17.
    Flatters SJ, Bennett GJ (2004) Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain 109:150–161CrossRefPubMedGoogle Scholar
  18. 18.
    De la Calle JL, Paíno CL (2002) A procedure for direct lumbar puncture in rats. Brain Res Bull 59:245–250CrossRefPubMedGoogle Scholar
  19. 19.
    Lee I, Park ES, Kim HK, Wang JG, Chung K, Chung JM (2006) A modified direct lumbar puncture method in rats. Soc Neurosci Abstr 835:20Google Scholar
  20. 20.
    Cheng KI, Lai CS, Wang FY, Wang HC, Chang LL, Ho ST, Tsai HP, Kwan AL (2011) Intrathecal lidocaine pretreatment attenuates immediate neuropathic pain by modulating Nav1.3 expression and decreasing spinal microglial activation. BMC Neurol 11:71CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Furue H, Narikawa K, Kumamoto E, Yoshimura M (1999) Responsiveness of rat substantia gelatinosa neurones to mechanical but not thermal stimuli revealed by in vivo patch-clamp recording. J Physiol 521:529–535CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Furue H (2012) In vivo blind patch-clamp recording technique. In: Okada Y (ed) Patch-clamp techniques. Springer, New YorkGoogle Scholar
  23. 23.
    Funai Y, Pickering EA, Uta D, Nishikawa K, Mori T, Asada A, Imoto K, Furue H (2014) Systemic dexmedetomidine augments inhibitory synaptic transmission in the superficial dorsal horn through activation of descending noradrenergic control: an in vivo patch-clamp analysis of analgesic mechanisms. Pain 155:617–628CrossRefPubMedGoogle Scholar
  24. 24.
    Price DD (1988) Psychological and neural mechanisms of pain. Raven Press, New YorkGoogle Scholar
  25. 25.
    Furue H, Katafuchi T, Yoshimura M (2007) In vivo patch-clamp technique. In: Walz W (ed) Patch-clamp analysis advanced techniques. Humana Press, TotowaGoogle Scholar
  26. 26.
    Moon HJ, Lim BS, Lee DI, Ye MS, Lee G, Min BI, Bae H, Na HS, Kim SK (2014) Effects of electroacupuncture on oxaliplatin-induced neuropathic cold hypersensitivity in rats. J Physiol Sci 64:151–156CrossRefPubMedGoogle Scholar
  27. 27.
    Yamamoto S, Ono H, Kume K, Ohsawa M (2016) Oxaliplatin treatment changes the function of sensory nerves in rats. J Pharmacol Sci 130:189–193CrossRefPubMedGoogle Scholar
  28. 28.
    Fürst S (1999) Transmitters involved in antinociception in the spinal cord. Brain Res Bull 48:129–141CrossRefPubMedGoogle Scholar
  29. 29.
    Saif MW, Reardon J (2005) Management of oxaliplatin-induced peripheral neuropathy. Ther Clin Risk Manag 1:249–258PubMedPubMedCentralGoogle Scholar
  30. 30.
    Renn CL, Carozzi VA, Rhee P, Gallop D, Dorsey SG, Cavaletti G (2011) Multimodal assessment of painful peripheral neuropathy induced by chronic oxaliplatin-based chemotherapy in mice. Mol Pain 7:29CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Derjean D, Bertrand S, Le Masson G, Landry M, Morisset V, Nagy F (2003) Dynamic balance of metabotropic inputs causes dorsal horn neurons to switch functional states. Nat Neurosci 6:274–281CrossRefPubMedGoogle Scholar
  32. 32.
    Attal N, Bouhassira D, Gautron M, Vaillant JN, Mitry E, Lepère C, Rougier P, Guirimand F (2009) Thermal hyperalgesia as a marker of oxaliplatin neurotoxicity: a prospective quantified sensory assessment study. Pain 144:245–252CrossRefPubMedGoogle Scholar
  33. 33.
    Drott J, Starkhammar H, Börjeson S, Berterö C (2014) Oxaliplatin induced neurotoxicity among patients with colorectal cancer: documentation in medical records—a pilot study. Open J Nurs 4:265–274CrossRefGoogle Scholar
  34. 34.
    Garraway SM, Hochman S (2001) Modulatory actions of serotonin, norepinephrine, dopamine, and acetylcholine in spinal cord deep dorsal horn neurons. J Neurophysiol 86:2183–2194PubMedGoogle Scholar
  35. 35.
    Kawasaki Y, Kumamoto E, Furue H, Yoshimura M (2003) Alpha 2 adrenoceptor-mediated presynaptic inhibition of primary afferent glutamatergic transmission in rat substantia gelatinosa neurons. Anesthesiology 98:682–689CrossRefPubMedGoogle Scholar
  36. 36.
    Jiang LY, Li SR, Zhao FY, Spanswick D, Lin MT (2010) Norepinephrine can act via α2-adrenoceptors to reduce the hyper-excitability of spinal dorsal horn neurons following chronic nerve injury. J Formos Med Assoc 109:438–445CrossRefPubMedGoogle Scholar
  37. 37.
    Kinoshita J, Takahashi Y, Watabe AM, Utsunomiya K, Kato F (2013) Impaired noradrenaline homeostasis in rats with painful diabetic neuropathy as a target of duloxetine analgesia. Mol Pain 9:59CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Pertovaara A (2013) The noradrenergic pain regulation system: a potential target for pain therapy. Eur J Pharmacol 716:2–7CrossRefPubMedGoogle Scholar
  39. 39.
    Wada T, Otsu T, Hasegawa Y, Mizuchi A, Ono H (1996) Characterization of alpha 1-adrenoceptor subtypes in rat spinal cord. Eur J Pharmacol 312:263–266CrossRefPubMedGoogle Scholar
  40. 40.
    Nicholas AP, Hökfelt T, Pieribone VA (1996) The distribution and significance of CNS adrenoceptors examined with in situ hybridization. Trends Pharmacol Sci 17:245–255CrossRefPubMedGoogle Scholar
  41. 41.
    Reddy SV, Maderdrut JL, Yaksh TL (1980) Spinal cord pharmacology of adrenergic agonist-mediated antinociception. J Pharmacol Exp Ther 213:525–533PubMedGoogle Scholar
  42. 42.
    Asano T, Dohi S, Ohta S, Shimonaka H, Iida H (2000) Antinociception by epidural and systemic α2-adrenoceptor agonists and their binding affinity in rat spinal cord and brain. Anesth Analg 90:400PubMedGoogle Scholar
  43. 43.
    Honda K, Koga K, Moriyama T, Koguchi M, Takano Y, Kamiya HO (2002) Intrathecal alpha2 adrenoceptor agonist clonidine inhibits mechanical transmission in mouse spinal cord via activation of muscarinic M1 receptors. Neurosci Lett 322:161–164CrossRefPubMedGoogle Scholar
  44. 44.
    Schechtmann G, Wallin J, Meyerson BA, Linderoth B (2004) Intrathecal clonidine potentiates suppression of tactile hypersensitivity by spinal cord stimulation in a model of neuropathy. Anesth Analg 99:135–139CrossRefPubMedGoogle Scholar
  45. 45.
    Reddy SV, Yaksh TL (1980) Spinal noradrenergic terminal system mediates antinociception. Brain Res 189:391–401CrossRefPubMedGoogle Scholar
  46. 46.
    Baba H, Goldstein PA, Okamoto M, Kohno T, Ataka T, Yoshimura M, Shimoji K (2000) Norepinephrine facilitates inhibitory transmission in substantia gelatinosa of adult rat spinal cord (part 2): effects on somatodendritic sites of GABAergic neurons. Anesthesiology 92:485–492CrossRefPubMedGoogle Scholar
  47. 47.
    North RA, Yoshimura M (1984) The actions of noradrenaline on neurones of the rat substantia gelatinosa in vitro. J Physiol 349:43–55CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lynch JJ 3rd, Wade CL, Zhong CM, Mikusa JP, Honore P (2004) Attenuation of mechanical allodynia by clinically utilized drugs in a rat chemotherapy-induced neuropathic pain model. Pain 110:56–63CrossRefPubMedGoogle Scholar
  49. 49.
    Park HJ, Kim YH, Koh HJ, Park CS, Kang SH, Choi JH, Moon DE (2012) Analgesic effects of dexmedetomidine in vincristine-evoked painful neuropathic rats. J Korean Med Sci 27:1411–1417CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Yeo JH, Yoon SY, Kim SJ, Oh SB, Lee JH, Beitz AJ, Roh DH (2016) Clonidine, an alpha-2 adrenoceptor agonist relieves mechanical allodynia in oxaliplatin-induced neuropathic mice; potentiation by spinal p38 MAPK inhibition without motor dysfunction and hypotension. Int J Cancer 138:2466–2476CrossRefPubMedGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan 2016

Authors and Affiliations

  1. 1.Department of PhysiologyCollege of Korean Medicine, Kyung Hee UniversitySeoulRepublic of Korea
  2. 2.Department of Information PhysiologyNational Institute for Physiological SciencesOkazakiJapan
  3. 3.School of Life ScienceThe Graduate University for Advanced Studies (SOKENDAI)OkazakiJapan

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