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Repetitive Treatment With Diluted Bee Venom Reduces Neuropathic Pain Via Potentiation of Locus Coeruleus Noradrenergic Neuronal Activity and Modulation of Spinal NR1 Phosphorylation in Rats

Published:January 05, 2012DOI:https://doi.org/10.1016/j.jpain.2011.10.012

      Abstract

      We previously demonstrated that a single injection of diluted bee venom (DBV) temporarily alleviates thermal hyperalgesia, but not mechanical allodynia, in neuropathic rats. The present study was designed to determine whether repetitive injection of DBV produces more potent analgesic effects on neuropathy-induced nociception and whether those effects are associated with increased neuronal activity in the locus coeruleus (LC) and with the suppression of spinal NMDA receptor NR1 subunit phosphorylation (pNR1). DBV (.25 mg/kg) was administered subcutaneously twice a day for 2 weeks beginning on day 15 post-chronic constrictive injury surgery. Pain responses were examined and potential changes in LC Fos expression and spinal pNR1 expression were determined. Repetitive DBV administration significantly reduced mechanical allodynia, as well as thermal hyperalgesia. The activity of LC noradrenergic neurons was increased and spinal pNR1 expression was significantly suppressed by repetitive DBV as compared with those of vehicle or single DBV injection. These suppressive effects of repetitive DBV on neuropathic pain and spinal pNR1 were prevented by intrathecal pretreatment of idazoxan, an alpha-2 adrenoceptor antagonist. These results indicate that repetitive DBV produces potent analgesic effects on neuropathic pain and this is associated with the activation of the LC noradrenergic system and with a reduction in spinal pNR1.

      Perspective

      The results of current study demonstrate that repetitive administration of DBV significantly suppresses neuropathic pain. Furthermore, this study provides mechanistic information that repetitive treatment of DBV can produce more potent analgesic effect than single DBV treatment, indicating a potential novel strategy for the management of chronic pain.

      Key words

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      References

        • Abbadie C.
        • Besson J.M.
        Chronic treatments with aspirin or acetaminophen reduce both the development of polyarthritis and Fos-like immunoreactivity in rat lumbar spinal cord.
        Pain. 1994; 57: 45-54
        • Bennett G.J.
        • Xie Y.K.
        A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.
        Pain. 1988; 33: 87-107
        • Billingham M.E.
        • Morley J.
        • Hanson J.M.
        • Shipolini R.A.
        • Vernon C.A.
        Letter: An anti-inflammatory peptide from bee venom.
        Nature. 1973; 245: 163-164
        • Bridges D.
        • Thompson S.W.
        • Rice A.S.
        Mechanisms of neuropathic pain.
        Br J Anaesth. 2001; 87: 12-26
        • Guerra de Hoyos J.A.
        • Andres Martin Mdel C.
        • Bassas y Baena de Leon E.
        • Vigara Lopez M.
        • Molina Lopez T.
        • Verdugo Morilla F.A.
        • Gonzalez Moreno M.J.
        Randomised trial of long term effect of acupuncture for shoulder pain.
        Pain. 2004; 112: 289-298
        • Hargreaves K.
        • Dubner R.
        • Brown F.
        • Flores C.
        • Joris J.
        A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.
        Pain. 1988; 32: 77-88
        • Huang C.
        • Hu Z.P.
        • Long H.
        • Shi Y.S.
        • Han J.S.
        • Wan Y.
        Attenuation of mechanical but not thermal hyperalgesia by electroacupuncture with the involvement of opioids in rat model of chronic inflammatory pain.
        Brain Res Bull. 2004; 63: 99-103
        • Hylden J.L.
        • Wilcox G.L.
        Intrathecal morphine in mice: A new technique.
        Eur J Pharmacol. 1980; 67: 313-316
        • Kim H.W.
        • Kwon Y.B.
        • Ham T.W.
        • Roh D.H.
        • Yoon S.Y.
        • Lee H.J.
        • Han H.J.
        • Yang I.S.
        • Beitz A.J.
        • Lee J.H.
        Acupoint stimulation using bee venom attenuates formalin-induced pain behavior and spinal cord fos expression in rats.
        J Vet Med Sci. 2003; 65: 349-355
        • Kim H.W.
        • Kwon Y.B.
        • Han H.J.
        • Yang I.S.
        • Beitz A.J.
        • Lee J.H.
        Antinociceptive mechanisms associated with diluted bee venom acupuncture (apipuncture) in the rat formalin test: Involvement of descending adrenergic and serotonergic pathways.
        Pharmacol Res. 2005; 51: 183-188
        • Kwon Y.B.
        • Kang M.S.
        • Han H.J.
        • Beitz A.J.
        • Lee J.H.
        Visceral antinociception produced by bee venom stimulation of the Zhongwan acupuncture point in mice: Role of alpha(2) adrenoceptors.
        Neurosci Lett. 2001; 308: 133-137
        • Kwon Y.B.
        • Lee J.D.
        • Lee H.J.
        • Han H.J.
        • Mar W.C.
        • Kang S.K.
        • Beitz A.J.
        • Lee J.H.
        Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses.
        Pain. 2001; 90: 271-280
        • Kwon Y.B.
        • Han H.J.
        • Beitz A.J.
        • Lee J.H.
        Bee venom acupoint stimulation increases Fos expression in catecholaminergic neurons in the rat brain.
        Mol Cells. 2004; 17: 329-333
        • Kwon Y.B.
        • Yoon S.Y.
        • Kim H.W.
        • Roh D.H.
        • Kang S.Y.
        • Ryu Y.H.
        • Choi S.M.
        • Han H.J.
        • Lee H.J.
        • Kim K.W.
        • Beitz A.J.
        • Lee J.H.
        Substantial role of locus coeruleus-noradrenergic activation and capsaicin-insensitive primary afferent fibers in bee venom’s anti-inflammatory effect.
        Neurosci Res. 2006; 55: 197-203
        • Lee J.H.
        • Kwon Y.B.
        • Han H.J.
        • Mar W.C.
        • Lee H.J.
        • Yang I.S.
        • Beitz A.J.
        • Kang S.K.
        Bee venom pretreatment has both an antinociceptive and anti-inflammatory effect on carrageenan-induced inflammation.
        J Vet Med Sci. 2001; 63: 251-259
        • Ramezani A.
        • Goudarzi I.
        • Lashkarbolouki T.
        • Ghorbanian M.T.
        • Elahdadi Salmani M.
        • Abrari K.
        Neuroprotective effects of the 17beta-estradiol against ethanol-induced neurotoxicity and oxidative stress in the developing male rat cerebellum: Biochemical, histological and behavioral changes.
        Pharmacol Biochem Behav. 2011; 100: 144-151
        • Raymond L.A.
        • Tingley W.G.
        • Blackstone C.D.
        • Roche K.W.
        • Huganir R.L.
        Glutamate receptor modulation by protein phosphorylation.
        J Physiol Paris. 1994; 88: 181-192
      1. Renn CL, Dorsey SG: The physiology and processing of pain: A review. AACN Clin Issues 16:277-290; quiz 413-275, 2005

        • Roh D.H.
        • Kwon Y.B.
        • Kim H.W.
        • Ham T.W.
        • Yoon S.Y.
        • Kang S.Y.
        • Han H.J.
        • Lee H.J.
        • Beitz A.J.
        • Lee J.H.
        Acupoint stimulation with diluted bee venom (apipuncture) alleviates thermal hyperalgesia in a rodent neuropathic pain model: Involvement of spinal alpha 2-adrenoceptors.
        J Pain. 2004; 5: 297-303
        • Roh D.H.
        • Kim H.W.
        • Yoon S.Y.
        • Kang S.Y.
        • Kwon Y.B.
        • Cho K.H.
        • Han H.J.
        • Ryu Y.H.
        • Choi S.M.
        • Lee H.J.
        • Beitz A.J.
        • Lee J.H.
        Bee venom injection significantly reduces nociceptive behavior in the mouse formalin test via capsaicin-insensitive afferents.
        J Pain. 2006; 7: 500-512
        • Roh D.H.
        • Kim H.W.
        • Yoon S.Y.
        • Seo H.S.
        • Kwon Y.B.
        • Han H.J.
        • Beitz A.J.
        • Lee J.H.
        Depletion of capsaicin-sensitive afferents prevents lamina-dependent increases in spinal N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation associated with thermal hyperalgesia in neuropathic rats.
        Eur J Pain. 2008; 12: 552-563
        • Roh D.H.
        • Kim H.W.
        • Yoon S.Y.
        • Seo H.S.
        • Kwon Y.B.
        • Han H.J.
        • Beitz A.J.
        • Lee J.H.
        Intrathecal clonidine suppresses phosphorylation of the N-methyl-D-aspartate receptor NR1 subunit in spinal dorsal horn neurons of rats with neuropathic pain.
        Anesth Analg. 2008; 107: 693-700
        • Sawynok J.
        • Reid A.
        Role of ascending and descending noradrenergic pathways in the antinociceptive effect of baclofen and clonidine.
        Brain Res. 1986; 386: 341-350
        • Somerfield S.D.
        • Brandwein S.
        Bee venom and adjuvant arthritis.
        J Rheumatol. 1988; 15: 1878
        • Tsuruoka M.
        • Arai Y.C.
        • Nomura H.
        • Matsutani K.
        • Willis W.D.
        Unilateral hindpaw inflammation induces bilateral activation of the locus coeruleus and the nucleus subcoeruleus in the rat.
        Brain Res Bull. 2003; 61: 117-123
        • Tsuruoka M.
        • Maeda M.
        • Nagasawa I.
        • Inoue T.
        Spinal pathways mediating coeruleospinal antinociception in the rat.
        Neurosci Lett. 2004; 362: 236-239
        • Willis W.D.
        Long-term potentiation in spinothalamic neurons.
        Brain Res Brain Res Rev. 2002; 40: 202-214
        • Woolf C.J.
        • Mannion R.J.
        Neuropathic pain: Aetiology, symptoms, mechanisms, and management.
        Lancet. 1999; 353: 1959-1964
        • Yoon S.Y.
        • Kwon Y.B.
        • Kim H.W.
        • Roh D.H.
        • Seo H.S.
        • Han H.J.
        • Lee H.J.
        • Beitz A.J.
        • Hwang S.W.
        • Lee J.H.
        Peripheral bee venom’s anti-inflammatory effect involves activation of the coeruleospinal pathway and sympathetic preganglionic neurons.
        Neurosci Res. 2007; 59: 51-59
        • Yoon S.Y.
        • Roh D.H.
        • Kwon Y.B.
        • Kim H.W.
        • Seo H.S.
        • Han H.J.
        • Lee H.J.
        • Beitz A.J.
        • Lee J.H.
        Acupoint stimulation with diluted bee venom (apipuncture) potentiates the analgesic effect of intrathecal clonidine in the rodent formalin test and in a neuropathic pain model.
        J Pain. 2009; 10: 253-263

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