[en] Besides its well-established efficacy in epilepsy, vagus nerve stimulation (VNS) may be of potential interest in pain treatment. It has, however, not yet been assessed in animal pain models with the devices and stimulation protocols used in humans. We have therefore studied in awake rats the effects of left cervical VNS on trigeminal nociception using an implantable electrode and stimulator (NCP-Cyberonics((R)). VNS was applied for 24 h at 2 mA intensity, 20 Hz frequency, 0.5 ms pulse width and a duty cycle of 20 s ON/18 s OFF. As a nociceptive stimulus, we injected formalin into the left mystacial vibrissae, assessed behaviour for 45 min and sacrificed the animals 45 min later. Fos-immunoreactive (Fos-Ir) neurons were counted in laminae I-II of trigeminal nucleus caudalis (TNC on both sides. We used three groups of control animals: VNS without formalin, formalin without VNS and sham VNS (implanted without stimulation or formalin). Whereas sham VNS had no significant effect, VNS alone increased Fos expression in ipsilateral TNC in addition to the expected increase in nucleus tractus solitarius. It also significantly attenuated the increase of Fos-Ir neurons observed in ipsilateral TNC laminae I-II after formalin injection. If the proper VNS effect on Fos-expression was subtracted, the reduction of formalin-induced nociceptor activation was 55%. VNS also reduced nociceptive behaviour on average by 96.1% during the early phase (0-6 min) and by 60.7% during the late phase (6-45 min) after the formalin injection. These results suggest that VNS applied with a device used in human therapy may have in awake rats a significant antinociceptive effect in a model of trigeminal pain. (C) 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.
Disciplines :
Surgery Anesthesia & intensive care Neurology Neurosciences & behavior
Author, co-author :
Bohotin, C.
Scholsem, M.
Multon, Sylvie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Neuro-anatomie
Martin, Didier ; Université de Liège - ULiège > Département des sciences cliniques > Neurochirurgie
Bohotin, V.
Schoenen, Jean ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Neuro-anatomie
Language :
English
Title :
Vagus nerve stimulation in awake rats reduces formalin-induced nociceptive behaviour and fos-immunoreactivity in trigeminal nucleus caudalis
Abbott F.V., Franklin K.B., Westbrook R.F. The formalin test: scoring properties of the first and second phases of the pain response in rats. Pain. 60:1995;91-102.
Aicher S.A., Lewis S.J., Randich A. Antinociception produced by electrical stimulation of vagal afferents: independence of cervical and subdiaphragmatic branches. Brain Res. 542:1991;63-70.
Alreja M., Mutalik P., Nayar U., Manchanda S.K. The formalin test: a tonic pain model in the primate. Pain. 20:1984;97-105.
Baulmann J., Spitznagel H., Herdegen T., Unger T., Culman J. Tachykinin receptor inhibition and c-Fos expression in the rat brain following formalin-induced pain. Neuroscience. 95:2000;813-820.
Ben-Menachem E., Hamberger A., Hedner T., Hammond E.J., Uthman B.M., Slater J., Treig T., Stefan H., Ramsay R.E., Wernicke J.F. Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures. Epilepsy Res. 20:1995;221-227.
Bereiter D.A., Bereiter D.F., Ramos M. Vagotomy prevents morphine-induced reduction in Fos-like immunoreactivity in trigeminal spinal nucleus produced after TMJ injury in a sex-dependent manner. Pain. 96:2002;205-213.
Berthoud H.R., Neuhuber W.L. Functional and chemical anatomy of the afferent vagal system. Auton Neurosci. 85:2000;1-17.
Bogduk N. Cervicogenic headache: anatomic basis and pathophysiologic mechanisms. Curr Pain Headache Rep. 5:2001;382-386.
Bossut D.F., Whitsel E.A., Maixner W. A parametric analysis of the effects of cardiopulmonary vagal electrostimulation on the digastric reflex in cats. Brain Res. 579:1992;253-260.
Bossut D.F., Maixner W. Effects of cardiac vagal afferent electrostimulation on the responses of trigeminal and trigeminothalamic neurons to noxious orofacial stimulation. Pain. 65:1996;101-109.
Cadet R., Aigouy L., Woda A. Sustained hyperalgesia can be induced in the rat by a single formalin injection and depends on the initial nociceptive inputs. Neurosci Lett. 156:1993;43-46.
Chandler M.J., Hobbs S.F., Bolser D.C., Foreman R.D. Effects of vagal afferent stimulation on cervical spinothalamic tract neurons in monkeys. Pain. 44:1991;81-87.
Chandler M.J., Zhang J., Foreman R.D. Vagal, sympathetic and somatic sensory inputs to upper cervical (C1-C3) spinothalamic tract neurons in monkeys. J Neurophysiol. 76:1996;2555-2567.
Chandler M.J., Zhang J., Qin C., Foreman R.D. Spinal inhibitory effects of cardiopulmonary afferent inputs in monkeys: neuronal processing in high cervical segments. J Neurophysiol. 87:2002;1290-1302.
Chase M.H., Nakamura Y., Torii S. Afferent vagal modulation of brain stem somatic reflex activity. Exp Neurol. 27:1970;534-544.
Chase M.H., Torii S., Nakamura Y. The influence of vagal afferent fiber activity on masticatory reflexes. Exp Neurol. 27:1970;545-553.
Clavelou P., Dallel R., Orliaguet T., Woda A., Raboisson P. The orofacial formalin test in rats: effects of different formalin concentrations. Pain. 62:1995;295-301.
Clavelou P., Pajot J., Dallel R., Raboisson P. Application of the formalin test to the study of orofacial pain in the rat. Neurosci Lett. 103:1989;349-353.
Coderre T.J., Vaccarino A.L., Melzack R. Central nervous system plasticity in the tonic pain response to subcutaneous formalin injection. Brain Res. 535:1990;155-158.
Coimbra F., Coimbra A. Dental noxious input reaches the subnucleus caudalis of the trigeminal complex in the rat, as shown by c-Fos expression upon thermal or mechanical stimulation. Neurosci Lett. 173:1994;201-204.
Dickenson A.H., Sullivan A.F. Subcutaneous formalin-induced activity of dorsal horn neurones in the rat: differential response to an intrathecal opiate administered pre or post formalin. Pain. 30:1987;349-360.
Dubuisson D., Dennis S.G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain. 4:1977;161-174.
Ellrich J., Messlinger K. Afferent input to the medullary dorsal horn from the contralateral face in rat. Brain Res. 826:1999;321-324.
Evans A.R., Jones S.L., Blair R.W. Effects of vagal afferent nerve stimulation on noxious heat-evoked Fos-like immunoreactivity in the rat lumbar spinal cord. J Comp Neurol. 22:1994;490-498.
Fanselow E.E., Reid A.P., Nicolelis M.A. Reduction of pentylenetetrazole-induced seizure activity in awake rats by seizure-triggered trigeminal nerve stimulation. J Neurosci. 20:2000;8160-8168.
Fromm G.H., Sato K., Nakata M. The action of GABAB antagonists in the trigeminal nucleus of the rat. Neuropharmacology. 31:1992;475-480.
Fu Q.G., Chandler M.J., McNeill D.L., Foreman R.D. Vagal afferent fibers excite upper cervical neurons and inhibit activity of lumbar spinal cord neurons in the rat. Pain. 51:1992;91-100.
Gilbert S.D., Clark T.M., Flores C.M. Antihyperalgesic activity of epibatidine in the formalin model of facial pain. Pain. 89:2001;159-165.
Goadsby P.J., Knight Y.E., Hoskin K.L. Stimulation of the greater occipital nerve increases metabolic activity in the trigeminal nucleus caudalis and cervical dorsal horn of the cat. Pain. 73:1997;23-28.
Hobbs S.F., Oh U.T., Chandler M.J., Foreman R.D. Cardiac and abdominal vagal afferent inhibition of primate T9-S1 spinothalamic cells. Am J Physiol. 257:1989;R889-R895.
Hobbs S.F., Oh U.T., Chandler M.J., Fu Q.G., Bolser D.C., Foreman R.D. Evidence that C1 and C2 propriospinal neurons mediate the inhibitory effects of viscerosomatic spinal afferent input on primate spinothalamic tract neurons. J Neurophysiol. 67:1992;852-860.
Hockfield S., Gobel S. An anatomical demonstration of projections to the medullary dorsal horn (trigeminal nucleus caudalis) from rostral trigeminal nuclei and the contra lateral caudal medulla. Brain Res. 252:1982;203-211.
Hoskin K.L., Bulmer D.C., Lasalandra M., Jonkman A., Goadsby P.J. Fos expression in the midbrain periaqueductal grey after trigeminovascular stimulation. J Anat. 198:2001;29-35.
Hosoi T., Okuma Y., Nomura Y. Electrical stimulation of afferent vagus nerve induces IL-1beta expression in the brain and activates HPA axis. Am J Physiol Regul Integr Comp Physiol. 279:2000;R141-R147.
Hou W.Y., Shyu B.C., Chen T.M., Lee J.W., Shieh J.Y., Sun W.Z. Intrathecally administered c-Fos antisense oligodeoxynucleotide decreases formalin-induced nociceptive behavior in adult rats. Eur J Pharmacol. 18:1997;17-26.
Imbe H., Dubner R., Ren K. Masseteric inflammation-induced Fos protein expression in the trigeminal interpolaris/caudalis transition zone: contribution of somatosensory-vagal-adrenal integration. Brain Res. 845:1999;165-175.
Ito S. Electrophysiological evidence for projections of myelinated and non-myelinated primary vagal afferents to the rat insular cortex. Neurosci Lett. 179:1994;29-32.
Ito S.I. Possible representation of somatic pain in the rat insular visceral sensory cortex:a field potential study. Neurosci Lett. 241:1998;171-174.
Janig W., Khasar S.G., Levine J.D., Miao F.J. The role of vagal visceral afferents in the control of nociception. Prog Brain Res. 122:2000;273-287.
Kerr F.W. Central relationships of trigeminal and cervical primary afferents in the spinal cord and medulla. Brain Res. 43:1972;561-572.
Khasar S.G., Miao F.J., Janig W., Levine J.D. Vagotomy-induced enhancement of mechanical hyperalgesia in the rat is sympathoadrenal-mediated. J Neurosci. 18:1988;3043-3049.
Khasar S.G., Miao J.P., Janig W., Levine J.D. Modulation of bradykinin-induced mechanical hyperalgesia in the rat by activity in abdominal vagal afferents. Eur J Neurosci. 10:1998;435-444.
Kirchner A., Birklein F., Stefan H., Handwerker H.O. Left vagus nerve stimulation suppresses experimentally induced pain. Neurology. 55:2000;1167-1171.
Leah J.D., Porter J., de Pommery J., Menetrey D., Weil Fuguzza J. Effect of acute stimulation on Fos expression in spinal neurons in the presence of persisting C-fiber activity. Brain Res. 719:1996;104-111.
Le Bars D., Dickenson A.H., Besson J.M. Diffuse noxious inhibitory controls (DNIC). Pain. 6:1979;305-327.
Le Bars D., Dickenson A.H., Besson J.M. Diffuse noxious inhibitory controls (DNIC). Pain. 6:1979;283-304.
Leong S., Liu H., Yeo J. Nitric oxide synthase and glutamate receptor immunoreactivity in the rat spinal trigeminal neurons expressing Fos protein after formalin injection. Brain Res. 855:2000;107-115.
Liporace J., Hucko D., Morrow R., Barolat G., Nei M., Schnur J., Sperling M. Vagal nerve stimulation: adjustments to reduce painful side effects. Neurology. 57:2001;885-886.
Maixner W., Randich A. Role of the right vagal nerve trunk in antinociception. Brain Res. 298:1984;374-377.
Maixner W., Bossut D.F., Whitsel E.A. Evaluation of vagal afferent modulation of the digastric reflex in cats. Brain Res. 560:1991;55-62.
Meller S.T., Lewis S.J., Ness T.J., Brody M.J., Gebhart G.F. Vagal afferent-mediated inhibition of a nociceptive reflex by intravenous serotonin in the rat. Brain Res. 30:(524):1990;90-100.
Miao F.J., Janig W., Dallman M.F., Benowitz N.L., Heller P.H., Basbaum A.I., Levine J.D. Role of vagal afferents and spinal pathways modulating inhibition of bradykinin-induced plasma extravasation by intrathecal nicotine. J Neurophysiol. 72:1994;1199-1207.
Miao F.J., Janig W., Jasmin L., Levine J.D. Spino-bulbo-spinal pathway mediating vagal modulation of nociceptive-neuroendocrine control of inflammation in the rat. J Physiol. 532:2001;811-822.
Michl T., Jocic M., Heinemann A., Schuligoi R., Holzer P. Vagal afferent signaling of a gastric mucosal acid insult to medullary, pontine, thalamic, hypothalamic and limbic, but not cortical, nuclei of the rat brain. Pain. 92:2001;19-27.
Nagamatsu N., Ikeda T., Terayama R., Nakamura T., Koganemaru M., Nishimori T. Effects of previous noxious stimulus applied to remote areas on noxious stimulus-evoked c-Fos expression in the rat trigeminal nucleus caudalis. Neurosci Res. 39:2001;293-298.
Naritoku D.K., Terry W.J., Helfert R.H. Regional induction of Fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Res. 22:1995;53-62.
Ness T.J., Fillingim R.B., Randich A., Backensto E.M., Faught E. Low intensity vagal nerve stimulation lowers human thermal pain thresholds. Pain. 86:2000;81-85.
Nishikawa Y., Koyama N., Yoshida Y., Yokota T. Activation of ascending antinociceptive system by vagal afferent input as revealed in the nucleus ventralis posteromedialis. Brain Res. 833:1999;108-111.
Partosoedarso E.R., Young R.L., Blackshaw L.A. GABA(B) receptors on vagal afferent pathways: peripheral and central inhibition. Am J Physiol Gastrointest Liver Physiol. 280:2000;658-668.
Qin C., Chandler M.J., Miller K.E., Foreman R.D. Responses and afferent pathways of superficial and deeper c(1)-c(2) spinal cells to intrapericardial algogenic chemicals in rats. J Neurophysiol. 85:2001;1522-1532.
Raboisson P., Dallel R., Clavelou P., Sessle B.J., Woda A. Effects of subcutaneous formalin on the activity of trigeminal brain stem nociceptive neurones in the rat. J Neurophysiol. 73:1995;496-505.
Randich A., Maixner W. [D-Ala2]-methionine enkephalinamide reflexively induces antinociception by activating vagal afferents. Pharmacol Biochem Behav. 21:1984;441-448.
Randich A., Aimone L.D., Gebhart G.F. Medullary substrates of descending spinal inhibition activated by intravenous administration of [D-Ala2]methionine enkephalinamide in the rat. Brain Res. 19:(411):1987;236-247.
Randich A., Aicher S.A. Medullary substrates mediating antinociception produced by electrical stimulation of the vagus. Brain Res. 445:1988;68-76.
Randich A., Thurston C.L., Ludwig P.S., Robertson J.D., Rasmussen C. Intravenous morphine-induced activation of vagal afferents: peripheral, spinal, and CNS substrates mediating inhibition of spinal nociception and cardiovascular responses. J Neurophysiol. 68:1992;1027-1045.
Randich A., Gebhart G.F. Vagal afferent modulation of nociception. Brain Res Brain Res Rev. 17:1992;77-99.
Redburn J.L., Leah J.D. Accelerated breakdown and enhanced expression of c-Fos in the rat brain after noxious stimulation. Neurosci Lett. 237:1997;97-100.
Ren K., Randich A., Gebhart G.F. Vagal afferent modulation of a nociceptive reflex in rats: involvement of spinal opioid and monoamine receptors. Brain Res. 19:(446):1988;285-294.
Ren K., Randich A., Gebhart G.F. Effects of electrical stimulation of vagal afferents on spinothalamic tract cells in the rat. Pain. 44:1991;311-319.
Ren K., Randich A., Gebhart G.F. Spinal serotonergic and kappa opioid receptors mediate facilitation of the tail flick reflex produced by vagal afferent stimulation. Pain. 45:(3):1991;321-329.
Ren K., Zhuo M., Randich A., Gebhart G.F. Vagal afferent stimulation-produced effects on nociception in capsaicin-treated rats. J Neurophysiol. 69:1993;1530-1540.
Ring H.A., White S., Costa D.C., Pottinger R., Dick J.P., Koeze T., Sutcliffe J.A. SPECT study of the effect of vagal nerve stimulation on thalamic activity in patients with epilepsy. Seizure. 9:2000;380-384.
Rutherfurd S.D., Widdop R.E., Sannajust F., Louis W.J., Gundlach A.L. Expression of c-fos and NGFI-A messenger RNA in the medulla oblongata of the anaesthetized rat following stimulation of vagal and cardiovascular afferents. Brain Res Mol Brain Res. 13:1992;301-312.
Saleh T.M., Cechetto D.F. Peptide changes in the parabrachial nucleus following cervical vagal stimulation. J Comp Neurol. 366:1996;390-405.
Sheng L.L., Nishiyama K., Honda T., Sugiura M., Yaginuma H., Sugiura Y. Suppressive effects of Neiting acupuncture on toothache: an experimental analysis on Fos expression evoked by tooth pulp stimulation in the trigeminal subnucleus pars caudalis and the periaqueductal gray of rats. Neurosci Res. 38:2000;331-339.
Strassman A.M., Vos B.P., Mineta Y., Naderi S., Borsook D., Burstein R. Fos-like immunoreactivity in the superficial medullary dorsal horn induced by noxious and innocuous thermal stimulation of facial skin in the rat. J Neurophysiol. 70:1993;1811-1821.
Takeda M., Tanimoto T., Ojima K., Matsumoto S. Suppressive effect of vagal afferents on the activity of the trigeminal spinal neurons related to the jaw-opening reflex in rats: involvement of the endogenous opioid system. Brain Res Bull. 47:1998;49-56.
Thies R., Foreman R.D. Descending inhibition of spinal neurons in the cardiopulmonary region by electrical stimulation of vagal afferent nerves. Brain Res. 207:1981;178-183.
Thies R., Foreman R.D. Inhibition and excitation of thoracic spinoreticular neurons by electrical stimulation of vagal afferent nerves. Exp Neurol. 82:1983;1-16.
Thurston C.L., Randich A. Electrical stimulation of the subdiaphragmatic vagus in rats: inhibition of heat-evoked responses of spinal dorsal horn neurons and central substrates mediating inhibition of the nociceptive tail flick reflex. Pain. 51:1992;349-365.
Thurston C.L., Randich A. Effects of vagal afferent stimulation on ON and OFF cells in the rostroventral medulla: relationships to nociception and arterial blood pressure. J Neurophysiol. 67:1992;180-196.
Thurston-Stanfield C.L., Ranieri J.T., Vallabhapurapu R., Barnes-Noble D. Role of vagal afferents and the rostral ventral medulla in intravenous serotonin-induced changes in nociception and arterial blood pressure. Physiol Behav. 67:1999;753-767.
Tjolsen A., Berge O.G., Hunskaar S., Rosland J.H., Hole K. The formalin test: an evaluation of the method. Pain. 51:1992;5-17.
Tokunaga A., Senba E., Manabe Y., Shida T., Ueda Y., Tohyama M. Orofacial pain increases mRNA level for galanin in the trigeminal nucleus caudalis of the rat. Peptides. 13:1992;1067-1072.
Van Laere K., Vonck K., Boon P., Brans B., Vandekerckhove T., Dierckx R. Vagus nerve stimulation in refractory epilepsy: SPECT activation study. J Nucl Med. 41:2000;1145-1154.
Vonck K., Boon P., Van Laere K., D'Havé M., Vandekerckhove T., O'Connor S., Brans B., Dierckx R., De Reuck J. Acute single photon emission computed tomographic study of vagus nerve stimulation in refractory epilepsy. Epilepsia. 41:2000;601-609.
Wakisaka S., Sasaki Y., Ichikawa H., Matsuo S. Increase in c-Fos-like immunoreactivity in the trigeminal nucleus complex after dental treatment. Proc Finn Dent Soc. 88:1992;551-555.
Zagon A. Does the vagus nerve mediate the sixth sense? Trends Neurosci. 24:2001;671-674.
