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Nociceptive Thresholds Are Controlled Through Spinal ОІ2-Subunit

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Nociceptive Thresholds Are Controlled Through Spinal ОІ2-Subunit PAINÒ 152 (2011) 2131–2137 www.elsevier.com/locate/pain Nociceptive thresholds are controlled through spinal b2-subunit-containing nicotinic acetylcholine receptors Ipek Yalcin a, Alexandre Charlet a,b, Matilde Cordero-Erausquin a, Luc-Henri Tessier a, Marina R. Picciotto c, ⇑ Rémy Schlichter a,b, Pierrick Poisbeau a,b, Marie-José Freund-Mercier a,b, Michel Barrot a, a Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France b Faculté des Sciences de la Vie, Université de Strasbourg, Strasbourg, France c Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT, USA Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. article info abstract Article history: Although cholinergic drugs are known to modulate nociception, the role of endogenous acetylcholine in Received 13 October 2010 nociceptive processing remains unclear. In the current study, we evaluated the role of cholinergic trans- Received in revised form 8 April 2011 mission through spinal b2-subunit-containing nicotinic acetylcholine receptors in the control of nocicep- Accepted 8 May 2011 tive thresholds. We show that mechanical and thermal nociceptive thresholds are significantly lowered ⁄ ⁄ in b2 -knockout (KO) mice. Using nicotinic antagonists in these mice, we demonstrate that b2 -nAChRs are responsible for tonic inhibitory control of mechanical thresholds at the spinal level. We further Keywords: hypothesized that tonic b ⁄-nAChR control of mechanical nociceptive thresholds might implicate GAB- Nicotinic 2 Aergic transmission since spinal nAChR stimulation can enhance inhibitory transmission. Indeed, the b -nAChRs 2 ⁄ Acetylcholine GABAA receptor antagonist bicuculline decreased the mechanical threshold in wild-type but not b2 -KO ⁄ ⁄ GABA mice, and the agonist muscimol restored basal mechanical threshold in b2 -KO mice. Thus, b2 -nAChRs Nociception appeared to be necessary for GABAergic control of nociceptive information. As a consequence of this ⁄ defective inhibitory control, b2 -KO mice were also hyperresponsive to capsaicin-induced C-fiber stimu- ⁄ lation. Our results indicate that b2 -nAChRs are implicated in the recruitment of inhibitory control of nociception, as shown by delayed recovery from capsaicin-induced allodynia, potentiated nociceptive response to inflammation and neuropathy, and by the loss of high-frequency transcutaneous electrical ⁄ nerve stimulation (TENS)–induced analgesia in b2 -KO mice. As high-frequency TENS induces analgesia ⁄ through Ab-fiber recruitment, these data suggest that b2 -nAChRs may be critical for the gate control of nociceptive information by non-nociceptive sensory inputs. In conclusion, acetylcholine signaling ⁄ through b2 -nAChRs seems to be essential for setting nociceptive thresholds by controlling GABAergic inhibition in the spinal cord. Ó 2011 Published by Elsevier B.V. on behalf of International Association for the Study of Pain. 1. Introduction horn, with a predominance of the a4, b2, and a7 subunits [8]. These nAChR subunits are found on primary afferent terminals [17] and Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand- intrinsic spinal interneurons [7]. Application of nicotinic agonists gated channels formed of five subunits surrounding a central cat- results in enhanced neurotransmission in the dorsal horn of the ionic pore [9]. These receptors are widely expressed in the central spinal cord [13,36,30]. and peripheral nervous system, where they contribute to many Although the effect of exogenous cholinomimetic drugs, such as neuronal functions, including development and degeneration nicotine or epibatidine, on nociceptive transmission in the spinal [44], cognitive functions [19], emotional and motivational pro- cord has been studied [6,8,31], the role of endogenous acetylcho- cesses [27,35], as well as nociception and pain processes [7,37]. line in nociceptive processing remains unclear. It has already been ⁄ The dorsal horn of the spinal cord plays an important role in the reported that nAChRs containing the b2-subunit (b2 -nAChR) con- reception, integration, and transmission of peripheral nociceptive tribute to nicotine-induced analgesia, as the ability of nicotine to ⁄ information. Most nAChR subunits are expressed in the dorsal attenuate thermal nociception is reduced in b2 -knockout (KO) mice [20]. However, acute nociceptive responses to heat in the ⇑ Corresponding author. Tel.: +33 3 68 85 14 50; fax: +33 3 88 61 33 47. tail-flick and hot-plate tests were not altered in these KO mice ⁄ E-mail address: [email protected] (M. Barrot). [20], suggesting that the endogenous stimulation of b2 -nAChRs 0304-3959/$36.00 Ó 2011 Published by Elsevier B.V. on behalf of International Association for the Study of Pain. doi:10.1016/j.pain.2011.05.022 2132 I. Yalcin et al. / PAINÒ 152 (2011) 2131–2137 might not be critical for setting these responses under basal condi- The latency to the first hind paw licking or withdrawal was taken tions. However, more recent pharmacological studies using nAC- as an index of nociceptive response. A cut-off time was set at 15 sec- ⁄ hRs antagonists suggest that acute blockade of b2 -nAChR activity onds to avoid damage to the paw. For the dynamic hot-plate (DHP) might induce thermal hyperalgesia [30]. test, mice were placed on the DHP (Bioseb, France) at 30 ± 0.1°C, In the current study, we used pharmacological and genetic ap- and the plate temperature was increased to 43°C with a computer- ⁄ proaches in KO mice to evaluate the role of spinal b2 -nAChR sub- controlled rate of 1°C/min as previously described [40]. During each units in the control of acute nociceptive sensitivity. Our results degree interval, we scored escape behavior (jumps). ⁄ reveal that b2 -nAChRs are critical for establishing mechanical and thermal nociceptive thresholds through endogenous choliner- 2.4. Sustained pain models gic and GABAergic networks. 2.4.1. Inflammatory pain 2. Methods Under isoflurane anesthesia, a volume of 10 ll of Complete Fre- und Adjuvant (CFA, Sigma-Aldrich, Saint Quentin Fallavier, France) 2.1. Animals was injected subcutaneously into the plantar surface of the right hindpaw using 50 ll Hamilton syringe with a 27-gauge needle. ⁄ Baseline threshold to mechanical stimuli was determined for each As a genetic approach to assess b2 -nAChR function, we used age- ⁄ animal before CFA injection and then measured 6, 24, and 48 hours matched, adult, wild-type or b2 -KO mice backcrossed for more than 10 generations onto the C57BL/6J background [28]. All mice were and 4 days after the injection using von Frey tests. male, except for the neuropathic allodynia study, for which one- third of the mice in each group were female. These experimental 2.4.2. Neuropathic pain mice were littermates from heterozygous breeding pairs and were Neuropathic pain was induced by placing a cuff around the right genotyped at weaning. The Pasteur Institute kindly provided breed- common sciatic nerve in mice as described previously [41]. Surgery ers through the Charles River mouse repository (St Germain sur was performed under ketamine/xylazine anesthesia (ketamine L’Arbresle France). Mice were group-housed four to five animals 17 mg/ml and xylazine 2.5 mg/ml; intraperitoneal [i.p.] adminis- per cage and maintained on a 12-hour light/dark cycle (lights on at tration, 4 ml/kg) (Centravet, Taden, France). The common branch 6 AM) with food and water available ad libitum. The dose–response of the right sciatic nerve was exposed and a 2-mm section of split studies were performed in C57BL/6J male mice (Charles River, St PE-20 polyethylene tubing (Harvard Apparatus, Les Ulis, France) Germain sur L’Arbresle France). The animal facilities are legally reg- was placed around it (Cuff group) [1]. Sham-operated mice under- istered for animal experimentation under Animal House Agreement went the same surgical procedure without cuff implantation B67-482-1/C67-482-1. All procedures were performed in accor- (Sham group). dance with the guidelines for animal experimentation of the Inter- national Association for the Study of Pain and the European 2.5. Transcutaneous electrical nerve stimulation Communities Council Directive 86/6609/EEC. Animals were lightly anesthetized by halothane inhalation and 2.2. Nociceptive tests: mechanical sensitivity the right hindlimb was prepared for electrode placement by shav- ing and cleaning the area with ethanol. Two silver electrodes cov- We evaluated the mechanical threshold by using von Frey hairs ered with conducting gel were placed at the surface of the right (Bioseb, Chaville, France) as previously described [3,41,42]. Mice hindlimb. Pulse duration was set at 250 microseconds. The inten- were placed in clear Plexiglas boxes (7 cm  9cm 7 cm) on an ele- sity was set at a sensory level, just below muscle contraction level vated mesh screen, and were allowed to habituate for 15 minutes (6–12 mA). Transcutaneous electrical nerve stimulation (TENS) before testing. Filaments were applied to the plantar surface of each was delivered at very high frequency (2000 Hz) for 20 minutes. hindpaw in a series of ascending forces. We approached the filament This procedure has been shown previously to recruit sensory Ab fi- toward the plantar surface slowly until it slightly bent at contact. At bers selectively [18,21]. After either the TENS procedure or light that point the pressure was immediately removed [24]. Each fila- anesthesia only (controls, No TENS), mice were placed in clear ment was tested five times per paw and the threshold was defined Plexiglas boxes on the elevated mesh screen and allowed to re- as three or more withdrawals observed among the five consecutive cover for approximately 30 minutes before mechanical sensitivity trials. The results were expressed in grams.The filaments (Bioseb) testing with von Frey hairs. used in the studies were labeled as follows: 0.008, 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1, 1.4, 2, 4, 6, 8, 10, and 15 grams.
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