Anti-allodynic effects following intrathecal administration of α1- and α2-adrenergic receptor agonists in a rat model of trigeminal neuropathic pain

Main Article Content

Kunihiro Nakai Aya Nakae Sosuke Oba Ko Hosokawa Takashi Mashimo Koichi Ueda

Abstract

The descending noradrenergic system inhibits nociception in the spinal cord. Spinal nerve injury triggers ectopic sprouting of sympathetic nerve fibers within dorsal root ganglia. Spinal α2-adrenoceptors, but not α1-adrenoceptors, exert an inhibitory effect in a rat model of spinal nerve ligation. However, trigeminal nerve injury does not induce sprouting of sympathetic nerve fibers in the trigeminal ganglion. In the present study, we analyzed the roles of α1- and α2-adrenoceptors in anti-allodynic effects following trigeminal nerve injury.

Chronic constriction injury to the infraorbital nerve (ION-CCI) with loose ligatures was used to establish a trigeminal neuropathic pain model. Allodynia was evaluated by applying von Frey filaments. The anti-allodynic effects after intrathecal administration of α1- and α2-adrenoceptor agonists and antagonists were examined.

Administration of the α1-adrenoceptor agonist phenylephrine (3, 10, and 30 μg) and α2-adrenoceptor agonist clonidine (3, 10, and 30 μg) resulted in dose-dependent anti-allodynic effects. Intrathecal administration of the α1-adrenoceptor antagonist prazosin (30 μg) and α2-adrenoceptor antagonist yohimbine (30 μg) did not alter the mechanical thresholds. Intrathecal pretreatment with prazosin (3 and 10 μg) reduced the anti-allodynic effects of the highest phenylephrine dose, while intrathecal pretreatment with yohimbine (3 and 10 μg) reduced the anti-allodynic effects of the highest clonidine dose.

Peripheral adrenergic modulation following nerve injury did not aggravate trigeminal neuropathic pain. These results differ from a previous rat neuropathic pain model of spinal nerve injury. In the ION-CCI rat model, the spinal α1- and α2-adrenoceptors played roles in spinal inhibition of trigeminal neuropathic pain.

Article Details

How to Cite
NAKAI, Kunihiro et al. Anti-allodynic effects following intrathecal administration of α1- and α2-adrenergic receptor agonists in a rat model of trigeminal neuropathic pain. Medical Research Archives, [S.l.], v. 2, n. 3, oct. 2015. ISSN 2375-1924. Available at: <http://www.journals.ke-i.org/index.php/mra/article/view/387>. Date accessed: 19 oct. 2017.
Keywords
infraorbital nerve, trigeminal nerve, α1- and α2-adrenergic receptor, orofacial neuropathic pain, nerve injury, sympathetic sprouting
Section
Research Articles

References

Ahn D, Kim Y, Park J. (1998). Central NO is involved in the antinociceptive action of intracisternal antidepressants in freely moving rats. Neurosci Lett, 243, 105–108.

Ali Z, Raja SN, Wesselmann U, Fuchs PN, Meyer RA, Campbell JN. (2000). Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain. Pain, 88, 161–168.

Ali Z, Ringkamp M, Hartke TV, Chien HF, Flavahan NA, Campbell JN, Meyer RA. (1999). Uninjured C-fiber nociceptors develop spontaneous activity and α-adrenergic sensitivity following L6 spinal nerve ligation in monkey. J Neurophysiol, 81, 455–466.

Aran S, Proudfit HK. (1990). Antinociceptive interactions between intrathecally administered α noradrenergic agonists and 5’-N-ethylcarboxamide adenosine. Brain Res, 519, 287–293.

Arner S, Meyerson BA. (1988). Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain, 33, 11–23.

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, 400–407.

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

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.

Banik RK, Sato J, Yajima H, Mizumura K. (2001). Differences between the Lewis and Sprague-Dawley rats in chronic inflammation induced norepinephrine sensitivity of cutaneous C-fiber nociceptors. Neurosci Lett, 299, 21–24.

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

Benoliel R, Eliav E, Tal M. (2001). No sympathetic nerve sprouting in rat trigeminal ganglion following painful and non-painful infraorbital nerve neuropathy. Neurosci Lett, 297, 151–154.

Bie B, Fields HL, Williams JT, Pan ZZ. (2003). Roles of α1- and α2-adrenoceptors in the nucleus raphe magnus in opioid analgesia and opioid abstinence-induced hyperalgesia. J Neurosci, 23, 7950–7957.

Bongenhielm U, Boissonade FM, Westermark A, Robinson PP, Fried K. (1999). Sympathetic nerve sprouting fails to occur in the trigeminal ganglion after peripheral nerve injury in the rat. Pain, 82, 283–288.

Bongenhielm U, Yates JM, Fried K, Robinson PP. (1998). Sympathectomy does not affect the early ectopic discharge from myelinated fibres in ferret inferior alveolar nerve neuromas. Neurosci Lett, 245, 89–92.

Bylund DB, Ray-Prenger C, Murphy TJ. (1988). Alpha2A and alpha2B adrenergic receptor subtypes: antagonist binding in tissues and cell lines containing only one subtype. J Pharmacol Exp Ther, 245, 600–607.

Cahusac PMB, Morris R, Hill RG. (1995). A pharmacological study of the modulation of neuronal and behavioural nociceptive responses in the rat trigeminal region. Brain Res, 700, 70–82.

Chen Y, Michaelis M, Janig W, Devor M. (1996). Adrenoceptor subtype mediating sympathetic-sensory coupling in injured sensory neurons. J Neurophysiol, 76, 3721–3730.

Choi B, Rowbotham MC. (1997). Effects of adrenergic receptor activation on post-herpetic neuralgia pain and sensory disturbances. Pain, 69, 55–63.

Chung K, Kim HJ, Na SK, Park MJ, Chung JM. (1993). Abnormalities of sympathetic innervation in the area of an injured peripheral nerve in a rat model of neuropathic pain. Neurosci Lett, 162, 85–88.

Danzebrink RM, Gebhart GF. (1990). Antinociceptive effects of intrathecal adrenoceptor agonists in a rat model of Visceral nociception. J Pharmacol Exp Ther, 253, 698-705

Davis KD, Treede RD, Raja SN, Meyer RA, Campbell JN. (1991). Topical application of clonidine relieves hyperalgesia in patients with symapathetically maintained pain. Pain, 47, 309–317.

Devor M, Jänig W, Michaelis M. (1994). Modulation of activity in the dorsal root ganglion neurons by sympathetic activation in nerve-injured rats. J Neurophysiol, 71, 38–47.

Drummond PD. (2009). α1-adrenoceptors augment thermal hyperalgesia in mildly burnt skin. Eur J pain, 13, 273–279.

Eisenach JC, Zhang Y, Duflo F. (2005). α2-adrenoceptors inhibit the intracellular Ca2+ response to electrical stimulation in normal and injured sensory neurons, with increased inhibition of calcitonin gene-related peptide expressing neurons after injury. Neuroscience, 131, 189–197.

Fang F, Proudfit HK. (1998). Antinociception produced by microinjection of morphine in the rat periaqueductal gray is enhanced in the foot, but not the tail, by intarathecal injection of α1-adrenoceptor antagonist. Brain Res, 790, 14–24.

Fang F, Proudfit HK. (1996). Spinal cholinergic and monoamine receptors mediate the antinociceptive effect of morphine microinjected in the periaquedutal gray on the rat tail, but not the feet. Brain Res, 722, 95–108.

Fisher B, Zornow MH, Yaksh TL, Peterson BM. (1991). Antinociceptive properties of intrathecal dexmedetomidine in rats. Eur J Pharmacol, 192, 221–225.

Fuchs PN, Meyer RA, Raja SN. (2001). Heat, but not mechanical hyperalgesia, following adrenergic injections in normal human skin. Pain, 90, 15–23.

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

Gracely RH, Lynch SA, Bennett GJ. (1992). Painful neuropathy: Altered central processing maintained dynamically by peripheral input. Pain, 51, 175–194.

Grelik C, Bennett GJ, Ribeiro-da-Silva A. (2005). Autonomic fibre sprouting and change in nociceptive sensory innervation in the rat lower lip skin following chronic constriction injury. Eur J Neurosci, 21, 2475–2487.

Grudt TJ, Williams JT, Travagli RA. (1995). Inhibition by 5-hydroxytryptamine and noradrenaline in substantia gelatinosa of guinea-pig spinal trigeminal nucleus. J Physiol, 485, 113–120.

Hayes AG, Skingle M, Tyers MB. (1986). Antagonism of alpha-adrenoceptor agonist-induced antinociception in the rat. Neuropharmacology, 25, 397–402.

Howe JR, Wang JY, Yaksh TL. (1983). Selective antagonism of the antinociceptive effect of intrathecally applied alpha adrenergic agonists by intrathecal prazosin and intrathecal yohimbine. J Pharmacol Exp Ther, 224, 552-558.

Idänpään-Heikkilä JJ, Guilbaud G. (1999). Phamacological studies on a rat model of trigeminal neuropathic pain: baclofen, but not carbamazepine, morphine or tricyclic antidepressants, attenuates the allodynia-like behaviour. Pain, 79, 281–290.

Janss AJ, Gebhart GF. (1987). Spinal monoaminergic receptors mediate the antinociception produced by glutamate in the medullary lateral reticular nucleus. J Neurosci, 7, 2862–2873.

Jones SL. (1991). Descending noradrenergic influences on pain. Prog Brain Res, 7, 381–394.

Kamisaki Y, Hamada T, Maeda K, Ishimura M, Itoh T. (1993). Presynaptic α2 adrenoceptors inhibit glutamate release from rat spinal cord synaptimes. J Neurocnem, 60, 522–526.

Kawasaki Y, Kumamoto E, Furue H, Yoshimura M. (2003). α2 adrenoceptor-mediated presynaptic inhibition of primary afferent glutamatergic transmission in rat substantia gelatinosa neurons. Anesthesiology, 98, 682–689.

Kim SK, Min BI, Kim JH, Hwang BG, Yoo GY, Park DS, Na HS. (2005). Individual differences in the sensitivity of cold allodynia to phentolamine in neuropathic rats. Eur J Pharmacol, 523, 64-66.

Korenman EM, Devor M. (1981). Ectopic adrenergic sensitivity in damaged peripheral nerve axons in the rat. Exp Neurol, 72, 63–81.

Latrémolière A, Mauborgne A, Masson J, Bourgoin S, Kayser V, Hamon M, Pohl M. (2008). Differential implication of proinflammatory cytokine interleukin-6 in the development of cephalic versus extracephalic neuropathic pain in rats. J Neurosci, 28, 8489–8501.

Lavand’homme PM, Ma W, Kock MD, Eisenach JC. (2002). Perinural α2A-adrenoceptor activation inhibits spinal cord nueroplasticity and tactile alldynia after nerve injury. Anesthesiology, 97, 972–980.

Lee DH, Liu X, Kim HT, Chung K, Chung JM. (1999). Receptor subtype mediating the adrenergic sensitivity of pain behavior and ectopic discharges in neuropathic Lewis rats. J Neurophysiol, 81, 2226–2233.

Lee YH, Ryu TG, Park SJ, Yang EJ, Jeon BH, Hur GM, Kim KJ. (2000). α1-adrenoceptors involvement in painful diabetic neuropathy: a role in allodynia. Neuroreport, 11, 1417-1420.

Leem JW, Gwak YS, Nam TS, Paik KS. (1997). Involvement of α2-adrenoceptors in mediating sympathetic excitation of injured dorsal root ganglion neurons in rats with spinal nerve ligation. Neurosci Lett, 234, 39–42.

Liu RH, Zhao ZQ. (1992). Selective blockage by yohimbine of descending spinal inhibition from lateral reticular nucleus but not from locus coeruleus in rats. Neurosci Lett, 142, 65-68.

MacFarlane BV, Wright A, O’Callaghan J, Benson HA. (1997). Chronic neuropathic pain and its control by drugs. Pharmacol Ther, 75, 1–19.

Mansikka H, Idänpään-Heikkilä JJ, Pertovaara A. (1996). Different roles of α2-adrenoceptors of the medulla versus the spinal cord in modulation of mustard oil-induced central hyperalgesia in rats. Eur J Pharmacol, 297, 19–26.

Mansikka H, Pertovaara A. (1995). The role of the medullary lateral reticular nucleus in spinal antinociception in rats. Brain Res Bull, 37, 633–638.

Matthews B. Autonomic mechanisms in oral sensations. (1989). Proc Finn Dent Soc, 85, 365–373.

McLachlan EM, Jänig W, Devor M, Michaelis M. (1993). Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature, 363, 543–546.

Nadelhaft I, Booth AM. (1984). The location and morphology of preganglionic neurons and the distribution of visceral afferents from the rat pelvic nerve: A horseradish peroxidase study. J Comp Neurol, 226, 238–245.

Nakai K, Nakae A, Oba S, Mashimo T, Ueda K. (2010a). 5-HT2C receptor agonists attenuate pain-related behaviour in a rat model of trigeminal neuropathic pain. Eur J Pain, 14(10), 999-106.

Nakai K, Nakae A, Oba S, Mashimo T, Ueda K. (2010b). P2X4 receptor expression in a rat model of trigeminal neuropathic pain. Neuroreport, 21, 559–563.

Nakae A, Nakai K, Tanaka T, Hagihira S, Shibata M, Ueda K, Mashimo T. (2008). The role of RNA editing of the serotonin 2C receptor in rat model of oro-facial neuropathic pain. Eur J Neurosci, 27, 2373–2379.

Ness TJ, Gebhart GF. (1988a). Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudoaffective reflexes in the rat. Brain Res, 450, 153–169.

Ness TJ, Gebhart GF. (1988b). Characterization of neurons responsive to colorectal distension in the T13-L2 spinal cord of the rat. J neurophysiol, 60, 1419–1438.

North RA, Yoshimura M. (1984). The actions of noradrenaline on neurons of the rat substantia gelatinosa in vitro. J Physiol, 349, 43–55.

O’halloran KD, Perl ER. (1997). Effects of partial nerve injury on the responses of C-fiber polymodal nociceptors to adrenergic agonists. Brain Res, 759, 233–240.

Olave MJ, Maxwell DJ. (2004). Axon terminals possessing α2C-adrenergic receptors densely innervate neurons in the rat spinal nucleus which respond to noxious stimulation. Neuroscience, 126, 391–403.

Orii R, Ohashi Y, Guo T, Nelson LE, Hashimoto T, Maze M, Fujinaga M. (2002). Evidence for the involvement of spinal cord α1-adrenoceptors in nitrous oxide-induced antinociceptive effects in Fisher rats. Anesthesiology, 97, 1458–1465.

Pan HL, Chen SR, Eisenach JC. (1999). Intrathecal clonidine alleviates allodynia in neuropathic rats. Anesthesiology, 90, 509–514.

Pan YZ, Li DP, Pan HL. (2002). Inhibition of glutamatergic synaptic input to spinal lamina IIo neurons by presynaptic α2-adrenergic receptors. J Neurophysiol, 87, 1938–1947.

Petrovaara A. (2006). Noradrenergic pain modulation. Prog Neurobiol, 80, 53–83.

Pertovaara A, Kalmari J. (2003). Comparison of the visceral antinociceptive effects of spinally administered MPV-2426 (Fadolmidine) and clonidine in the rat. Anesthesiology, 98, 189–194.

Petrovaara A, Hämäläinen MM, Kauppila T, Mercke E, Carlson S. (1994). Dissociaton of the α2-adrenergic antinociception from sedation following microinjection of medetomidine into the locus coeruleus in rats. Pain, 57, 207–215.

Piao ZG, Cho IH, Park CK, Hong JP, Choi SY, Lee SJ, Lee S, Park K, Kim JS, Oh SB. (2006). Activation of glia and microglia p38 MAPK in medullary dorsal horn contributes to tactile hypersensivity following trigeminal sensory nerve injury. Pain, 121, 219–231.

Post CP, Gordh T, Minor BG, Archer T, Freedman J. (1987). Antinociceptive effects and spinal cord tissue concentrations after intrathecal injection of guanfacine or clonidine into rats. Anesth Analg, 66, 317–324.

Proudfit HK. (1988). Pharmacologic evidence for the modulation of nociception by noradrenergic neurons. Prog Brain Res, 77, 357–370.

Ramer MS, Bisby MA. (1997). Rapid sprouting of sympathetic axons in dorsal root ganglia of rats with a chronic constriction injury. Pain, 70, 237–244.

Reddy SVR, Maderdrut JL, Yaksh TL. (1980). Spinal cord pharmacology of adrenergic agonist-mediated antinociception. J Pharmacol Exp Ther, 213, 525-533.

Ren Y, Zou X, Fang L, Lin Q. (2005). Sympathetic
modulation of activity in Aδ- and C-primary nociceptive afferents after intradermal injection of capsaicin in rats. J Neurophysiol, 93, 365-377.

Ruocco I, Cuello AC, Ribeiro-da-Silva A. (2000). Peripheral nerve injury leads to the establishment of a novel pattern of sympathetic fibre innervation in the rat skin. J Comp Neurol, 422, 287-296.

Solomon RE, Brody MJ, Gebhart GF. (1989). Pharmacological characterization of alpha adrenoceptors involved in the antinociceptive and cardiovascular effects of intrathecally administered clonidine. J Pharmacol Exp Ther, 251, 27-38.

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, 515–526.

Takano Y, Yaksh TL. (1992). Characterization of the pharmacology of intrathecally administered alpha-2 agonists and antagonists in rats. J Pharmacol Exp Ther, 261, 764-772.

Tasker RAR, Connell BJ, Yole MJ. (1992). Systemic injections of alpha-1 adrenergic agonists produce antinociception in the formalin test. Pain, 49, 383–391.
Torebjörk E, Wahren L, Wallin G, Hallin G, Koltzenburg M. (1995). Noadrenaline-evoked pain in neuralgia. Pain, 63, 11–20.

Tracey DJ, Cunningham JE, Romm MA. (1995). Peripheral hyperalgesia in experimental neuropathy: mediation by alpha-2-adrenoceptors on post-ganglionic sympathetic terminals. Pain, 60, 317–327.

Tsuruoka M, Willis WD. (1996). Bilateral lesions in the area of the nucleus locus coeruleus affect the development of hyperalgesia during carrageenan-induced inflammation. Brain Res, 726, 233–236.

Vos BP, Strassman AM, Maciewicz,RJ. (1994). Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat’s infraorbital nerve. J Neurosci, 14, 2708–2723.

Wang J, Ren Y, Zou X, Fang L, Willis WD, Lin Q. (2004). Sympathetic influence on capsaicin-evoked enhancement of dorsal root reflexes in rats. J Neurophysiol, 92, 2017–2026.

Wang XM, Zhang ZJ, Bains R, Mokha SS. (2002). Effects of antisense knock-down of α2a- and α2c-adrenoceptors on the antinociceptive action of clonidine on trigeminal nociception in the rat. Pain, 98, 27–35.

Wei H, Pertovaara A. (2006). Spinal and pontine α2-adrenoceptors have opposite effects on pain-related behavior in the neuropathic rat. Eur J Pharmacol, 551, 41–49.

Wei H, Pertovaara A. (1997). Peripherally administered α2-adrenoceptor agonist in the modulation of chronic allodynia induced by spinal nerve ligation in the rat. Anesth Analg, 85, 1122–1127.

Xu M, Kontinen VK, Kalso E. (2000). Effects of radolmidine, a novel α2-adrenergic agonist compared with dexmedetomidine in different pain models in the rat. Anesthesiology, 93, 473–481.

Yaksh TL, Porgel JW, Lee YW, Chaplan SR. (1995). Reversal of nerve ligation-induced allodynia by spinal alpha-2 adrenoceptor agonists. J Pharmacol Exp Ther, 272, 207-214.

Yaksh T, Rudy T. (1976). Chronic catheterization of spinal subarachnoid space. Physiol Behav, 17, 1031–1036.

Yen LD, Bennett GJ, Ribeiro-da-silva A. (2006). Sympathetic sprouting and Changes in nociceptive sensory innervation in the glabrous skin of the rat hind paw following partial peripheral nerve injury. J Comp Neurol, 495, 679-690.

Yoshimura M, Furue H. (2006). Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord. J Phamacol Sci, 101, 107–117.

Yuan WX, Chen SR, Chen H, Pan HL. (2009). Stimulation of α1-adrenoceptors reduces glutamatergic synaptic input from primary afferents through GABAA receptors and T-type Ca2+ channels. Neuroscience, 158, 1616–1624.

Zhang JM, Song XJ, LaMotte RH. (1997). An in vitro study of ectopic discharge generation and adrenergic sensitivity in the intact, nerve-injured rat dorsal root ganglion. Pain, 72, 51–57.

Zhang KM, Wang XM, Peterson AM, Chen WY, Mokha SS. (1998). α2-adrenoceptors modulate NMDA-evoked responses of neurons in superficial and deeper dorsal horn of the medulla. J Neurophysiol, 80, 2210–2214.

Zimmermann M. (1983). Ethical guidelines for investigations of experimental pain in conscious animals. Pain, 16, 109–110.

Most read articles by the same author(s)

Obs.: This plugin requires at least one statistics/report plugin to be enabled. If your statistics plugins provide more than one metric then please also select a main metric on the admin's site settings page and/or on the journal manager's settings pages.