Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors

Wei Xiong, Tanxing Cui, Kejun Cheng, Fei Yang, Shao-Rui Chen, Dan Willenbring, Yun Guan, Hui-Lin Pan, Ke Ren, Yan Xu, Li Zhang, Wei Xiong, Tanxing Cui, Kejun Cheng, Fei Yang, Shao-Rui Chen, Dan Willenbring, Yun Guan, Hui-Lin Pan, Ke Ren, Yan Xu, Li Zhang

Abstract

Certain types of nonpsychoactive cannabinoids can potentiate glycine receptors (GlyRs), an important target for nociceptive regulation at the spinal level. However, little is known about the potential and mechanism of glycinergic cannabinoids for chronic pain treatment. We report that systemic and intrathecal administration of cannabidiol (CBD), a major nonpsychoactive component of marijuana, and its modified derivatives significantly suppress chronic inflammatory and neuropathic pain without causing apparent analgesic tolerance in rodents. The cannabinoids significantly potentiate glycine currents in dorsal horn neurons in rat spinal cord slices. The analgesic potency of 11 structurally similar cannabinoids is positively correlated with cannabinoid potentiation of the α3 GlyRs. In contrast, the cannabinoid analgesia is neither correlated with their binding affinity for CB1 and CB2 receptors nor with their psychoactive side effects. NMR analysis reveals a direct interaction between CBD and S296 in the third transmembrane domain of purified α3 GlyR. The cannabinoid-induced analgesic effect is absent in mice lacking the α3 GlyRs. Our findings suggest that the α3 GlyRs mediate glycinergic cannabinoid-induced suppression of chronic pain. These cannabinoids may represent a novel class of therapeutic agents for the treatment of chronic pain and other diseases involving GlyR dysfunction.

Figures

Figure 1.
Figure 1.
Suppression of inflammatory pain by CBD and DH-CBD in mice. (A) Time course of heat pain hypersensitivity in mice after 20 µl CFA paw injection (1:4 in saline). Each data point represents the mean from 10–15 mice. (B) The analgesic effect of i.p. (50 mg/kg, n = 10) and i.t. (50 µg, n = 10) injection of DH-CBD or vehicle in mice 2 h after CFA injection. (C) The analgesic effect of the repeated application of i.p. injection of 50 mg/kg DH-CBD (n = 10) in mice after CFA injection. Note that the analgesic effect was nearly identical after repeated applications of DH-CBD during a period of two consecutive days after CFA injection. (D) Traces of IGly in the absence and presence of 1 µM DH-CBD and 1 µM CBD in HEK 293 cells expressing the α3 GlyRs. (E) Time course of CBD- (n = 7) and DH-CBD (n = 9)–induced potentiation on IGly in HEK 293 cells expressing the α3 GlyRs. (F) Dose-dependent analgesic effects of CBD (n = 10) and DH-CBD (n = 10) applied i.p. and i.t. in mice with CFA paw injection. Data are representative of two to three independent experiments (*, P < 0.05; ***, P < 0.001) and expressed as mean ± SEM.
Figure 2.
Figure 2.
DH-CBD potentiation of IGly in spinal neurons and suppression of inflammatory pain in rats. (A) Original recordings showing currents activated by puff application of 30 µM glycine to lamina II neurons with and without sustained DH-CBD application in rat spinal cord slices. 1 µM strychnine, a specific GlyR antagonist, was used to determine whether GlyRs are the target that mediates the DH-CBD–induced potentiation. (B) Bar graphs of DH-CBD–induced potentiation on IGly of spinal lamina II neurons (n = 7). (C and D) Effect of i.t. application of DH-CBD or vehicle on the ipsilateral (C) and contralateral (D) PWL to noxious heat stimulation in rats before and after intraplantar CFA injection (n = 6–7). (E and F) As in C and D, but rats were subjected to punctuate mechanical stimuli (n = 8). Data are representative of three (A and B) and two (C–F) independent experiments (*, P < 0.05; **, P < 0.01; ***, P < 0.001, post-drug vs. pre-drug) and expressed as mean ± SEM.
Figure 3.
Figure 3.
DH-CBD suppression of neuropathic pain in rats. (A) Time courses of the ipsilateral and contralateral PWT to mechanical stimulation after the fifth lumbar SNL in rats (n = 12). ***, P < 0.001, as compared with pre-SNL. (B and C) The analgesic effect of i.t. application of DH-CBD at 100 µg on PWT to mechanical stimulation (B) or heat stimulation (C) on day 14 after SNL (n = 12). *, P < 0.05; **, P < 0.01; ***, P < 0.001, as compared with pre DH-CBD. Data are representative of three independent experiments and expressed as mean ± SEM.
Figure 4.
Figure 4.
DH-CBD rescue of PGE2-induced inhibition of the α3 GlyRs and chronic pain. (A) Trace records of IGly in HEK 293 cells coexpressing EP2 receptors with either the α3 or α1 GlyRs before and after sustained PGE2 application. (B) Time courses of IGly in the cells coexpressing EP2 receptors with either the α3 (n = 6) or α1 (n = 5) GlyRs after sustained PGE2 application. ***, P < 0.001 (α1 vs. α3). (C) Trace records of IGly in cells coexpressing EP2 receptors with the α3 GlyRs without and with DH-CBD after sustained PGE2 application. (D) Time courses of DH-CBD potentiation of IGly in cells coexpressing the α3 GlyRs and EP2Rs after sustained PGE2 application (n = 6). ***, P < 0.001 as compared with vehicle application. (E) Time courses of PWL to thermal stimulation before, during, and after i.t. PGE2 injection in WT and α3−/− mice (n = 10). ***, P < 0.001, as compared with the WT mice. (F) The analgesic effect of 50 mg/kg DH-CBD i.p. (n = 10) on PWL to thermal stimulation after i.t. PGE2 injection. *, P < 0.05; ***, P < 0.001, as compared with i.p. vehicle (n = 10). Data are representative of two independent experiments and expressed as mean ± SEM.
Figure 5.
Figure 5.
Antagonism of DD-CBD to DH-CBD–induced potentiation of IGly and analgesia in inflammatory pain. (A) Structures of DH-CBD and DD-CBD. Trace records of IGly in HEK 293 cells expressing the α3 GlyRs without and with co-application of DD-CBD and DH-CBD. (B) DD-CBD inhibition of DH-CBD–induced potentiation of IGly in HEK 293 cells expressing the α3 GlyRs (n = 6). (C) The concentration-response curves of DH-CBD–induced potentiation of IGly without and with 1 µM DD-CBD (n = 5–7). (D) The effect of i.t. and i.p. application of DD-CBD on PWL to thermal stimulation after CFA paw injection in mice (n = 7–10). (E) Dose-dependent inhibition of i.p. DH-CBD–induced analgesic effect by i.p. application of DD-CBD in post-CFA mice (n = 7–10). (F) Dose-dependent inhibition of i.p. DH-CBD–induced analgesic effect by i.t. application of DD-CBD in post-CFA mice (n = 8–10). *, P < 0.05; ***, P < 0.001, as compared with vehicle injection. Data are representative of two independent experiments and expressed as mean ± SEM.
Figure 6.
Figure 6.
A decrease in CBD and DH-CBD–induced analgesia in the α3−/− mice but not in the CB1−/− and CB2 −/− mice. (A and B) The analgesic effect of 50 mg/kg CBD i.p. (A) or 50 mg/kg DH-CBD i.p. (B) on PWL to thermal stimulation after CFA injection in the α3−/− mice (n = 9–10). ***, P < 0.001, as compared with WT mice. (C and D) The analgesic effect of 50 mg/kg CBD i.p. (C) or 50 mg/kg DH-CBD i.p. (D) on PWL to thermal stimulation after CFA injection in the CB1−/− mice (n = 6). (E and F) The analgesic effect of 50 mg/kg CBD i.p. (E) or 50 mg/kg DH-CBD i.p. (F) on PWL to thermal stimulation after CFA injection in the CB2−/− mice (n = 6). Data are representative of two independent experiments and expressed as mean ± SEM.
Figure 7.
Figure 7.
Correlation analysis: relationships between cannabinoid potentiation and cannabinoid-induced analgesic and psychoactive effects. Correlation analysis: (A) Cannabinoid (1 µM)-induced potentiation of IGly versus the analgesic potency (percent changes of PWL) of 50 mg/kg cannabinoids i.p. in CFA-induced inflammatory pain (linear regression, n = 11). (B and C) The Ki values of cannabinoid binding affinity for CB1 receptors (B) or CB2 receptors (C) versus the analgesic potency of cannabinoids. (D–F) Cannabinoid (1 µM)-induced potentiation of IGly versus the effects of 50 mg/kg cannabinoids i.p. on body temperature (D), locomotor activity (E), or rotarod performance (F). (G–I) The analgesic potency of 50 mg/kg cannabinoids i.p. versus the effect of cannabinoids on body temperature (G), locomotor activity (H), or rotarod performance (I). Data are representative of two to three independent experiments.
Figure 8.
Figure 8.
NMR analysis: a direct interaction between CBD and S296-containing domain of α3 GlyR. (A) A homology model of α3 GlyR-TM domain structure derived from the high-resolution NMR structure of α1 GlyR TM domains. S296 residue is highlighted in red. (B) Contour plots of the S296 resonance in the HSQC spectrum of the α3 GlyR TM domains in LPPG micelles as a function of CBD concentrations: red, 0 µM; orange, 5 µM; blue, 105 µM; and green, 546 µM. (C) Strip plots of the 2D 1H-1H NOESY spectra in the absence and presence of α3 GlyR TM domains, showing an unambiguous cross peak between the aromatic protons of CBD and the Hβ of S296. (D) Side views of a proposed binding interaction between CBD and the α3 GlyR-TM involving the S296, as revealed by a molecular dynamic simulation of 20 ns. The S296 residue is indicated in red and CBD is indicated in yellow. Lipids surrounding the S296-containing domain are indicated in blue. (E) Traces of CBD-induced potentiation on IGly in HEK 293 cells expressing the WT (n = 5) and mutant S296A (n = 6) α3 GlyRs. (F) The concentration-response curves of CBD-induced potentiation of the α3 GlyRs. ***, P < 0.001 (WT vs. S296A). Data are representative of two independent experiments and expressed as mean ± SEM.
Figure 9.
Figure 9.
The effect of DH-CBD on α3 GlyR gating kinetics and agonist affinity. (A) Traces of currents activated by 1 mM glycine in HEK 293 cells expressing WT or S296A mutant α3 GlyRs in the absence and presence of 3 µM DH-CBD. Bar graph shows the mean activation time constant (n = 6–9). Asterisks indicate a significant difference as compared with vehicle (*, P < 0.05). (B) Traces of currents during a washout after a 10-ms application of 1 mM glycine in the absence and presence of 3 µM DH-CBD. The bar graph shows mean deactivation time constants (n = 6–7). The asterisk indicates a significant difference as compared with vehicle (***, P < 0.001). (C) The glycine concentration-response curves in the absence (n = 6) and presence of 1 µM (n = 8) and 10 µM (n = 5) DH-CBD. Data are representative of two independent experiments and expressed as mean ± SEM.

References

    1. Ahmadi S., Lippross S., Neuhuber W.L., Zeilhofer H.U. 2002. PGE(2) selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons. Nat. Neurosci. 5:34–40 10.1038/nn778
    1. Ahrens J., Demir R., Leuwer M., de la Roche J., Krampfl K., Foadi N., Karst M., Haeseler G. 2009a. The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function. Pharmacology. 83:217–222 10.1159/000201556
    1. Ahrens J., Leuwer M., Demir R., Krampfl K., de la Roche J., Foadi N., Karst M., Haeseler G. 2009b. Positive allosteric modulatory effects of ajulemic acid at strychnine-sensitive glycine alpha1- and alpha1beta-receptors. Naunyn Schmiedebergs Arch. Pharmacol. 379:371–378 10.1007/s00210-008-0366-8
    1. Bai G., Wei D., Zou S., Ren K., Dubner R. 2010. Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia. Mol. Pain. 6:51 10.1186/1744-8069-6-51
    1. Brooks B.R., Brooks C.L., III, Mackerell A.D., Jr, Nilsson L., Petrella R.J., Roux B., Won Y., Archontis G., Bartels C., Boresch S., et al. 2009. CHARMM: the biomolecular simulation program. J. Comput. Chem. 30:1545–1614 10.1002/jcc.21287
    1. Buckley N.E., McCoy K.L., Mezey E., Bonner T., Zimmer A., Felder C.C., Glass M., Zimmer A. 2000. Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. Eur. J. Pharmacol. 396:141–149 10.1016/S0014-2999(00)00211-9
    1. Burns T.L., Ineck J.R. 2006. Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain. Ann. Pharmacother. 40:251–260 10.1345/aph.1G217
    1. Canlas C.G., Ma D., Tang P., Xu Y. 2008. Residual dipolar coupling measurements of transmembrane proteins using aligned low-q bicelles and high-resolution magic angle spinning NMR spectroscopy. J. Am. Chem. Soc. 130:13294–13300 10.1021/ja802578z
    1. Chaplan S.R., Bach F.W., Pogrel J.W., Chung J.M., Yaksh T.L. 1994. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods. 53:55–63 10.1016/0165-0270(94)90144-9
    1. Cheng M.H., Liu L.T., Saladino A.C., Xu Y., Tang P. 2007. Molecular dynamics simulations of ternary membrane mixture: phosphatidylcholine, phosphatidic acid, and cholesterol. J. Phys. Chem. B. 111:14186–14192 10.1021/jp075467b
    1. Costa B. 2007. On the pharmacological properties of Delta9-tetrahydrocannabinol (THC). Chem. Biodivers. 4:1664–1677 10.1002/cbdv.200790146
    1. Costa B., Trovato A.E., Comelli F., Giagnoni G., Colleoni M. 2007. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur. J. Pharmacol. 556:75–83 10.1016/j.ejphar.2006.11.006
    1. Delaglio F., Grzesiek S., Vuister G.W., Zhu G., Pfeifer J., Bax A. 1995. NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J. Biomol. NMR. 6:277–293 10.1007/BF00197809
    1. Demir R., Leuwer M., de la Roche J., Krampfl K., Foadi N., Karst M., Dengler R., Haeseler G., Ahrens J. 2009. Modulation of glycine receptor function by the synthetic cannabinoid HU210. Pharmacology. 83:270–274 10.1159/000209291
    1. Dixon W.J. 1980. Efficient analysis of experimental observations. Annu. Rev. Pharmacol. Toxicol. 20:441–462 10.1146/annurev.pa.20.040180.002301
    1. Dobos I., Toth K., Kekesi G., Joo G., Csullog E., Klimscha W., Benedek G., Horvath G. 2003. The significance of intrathecal catheter location in rats. Anesth. Analg. 96:487–492
    1. Eswar N., Webb B., Marti-Renom M.A., Madhusudhan M.S., Eramian D., Shen M.Y., Pieper U., Sali A. 2007. Comparative protein structure modeling using MODELLER. Curr. Protoc. Protein Sci. Chapter 2:Unit 2.9
    1. Foadi N., Leuwer M., Demir R., Dengler R., Buchholz V., de la Roche J., Karst M., Haeseler G., Ahrens J. 2010. Lack of positive allosteric modulation of mutated alpha(1)S267I glycine receptors by cannabinoids. Naunyn Schmiedebergs Arch. Pharmacol. 381:477–482 10.1007/s00210-010-0506-9
    1. Grossman M.L., Basbaum A.I., Fields H.L. 1982. Afferent and efferent connections of the rat tail flick reflex (a model used to analyze pain control mechanisms). J. Comp. Neurol. 206:9–16 10.1002/cne.902060103
    1. Guan Y., Johanek L.M., Hartke T.V., Shim B., Tao Y.X., Ringkamp M., Meyer R.A., Raja S.N. 2008. Peripherally acting mu-opioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injury. Pain. 138:318–329 10.1016/j.pain.2008.01.004
    1. Hargreaves K., Dubner R., Brown F., Flores C., Joris J. 1988. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 32:77–88 10.1016/0304-3959(88)90026-7
    1. Harrison C. 2011. Analgesia: Inhibiting neuropathic pain. Nat. Rev. Drug Discov. 10:176 10.1038/nrd3396
    1. Harvey R.J., Depner U.B., Wässle H., Ahmadi S., Heindl C., Reinold H., Smart T.G., Harvey K., Schütz B., Abo-Salem O.M., et al. 2004. GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization. Science. 304:884–887 10.1126/science.1094925
    1. Harvey V.L., Caley A., Müller U.C., Harvey R.J., Dickenson A.H. 2009. A selective role for alpha3 subunit glycine receptors in inflammatory pain. Front. Mol. Neurosci. 2:14 10.3389/neuro.02.014.2009
    1. Hejazi N., Zhou C., Oz M., Sun H., Ye J.H., Zhang L. 2006. Delta9-tetrahydrocannabinol and endogenous cannabinoid anandamide directly potentiate the function of glycine receptors. Mol. Pharmacol. 69:991–997
    1. Hösl K., Reinold H., Harvey R.J., Müller U., Narumiya S., Zeilhofer H.U. 2006. Spinal prostaglandin E receptors of the EP2 subtype and the glycine receptor alpha3 subunit, which mediate central inflammatory hyperalgesia, do not contribute to pain after peripheral nerve injury or formalin injection. Pain. 126:46–53 10.1016/j.pain.2006.06.011
    1. Howlett A.C., Barth F., Bonner T.I., Cabral G., Casellas P., Devane W.A., Felder C.C., Herkenham M., Mackie K., Martin B.R., et al. 2002. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 54:161–202 10.1124/pr.54.2.161
    1. Huestis M.A., Pertwee R.G. 2005. Pharmacokinetics and Metabolism of the Plant Cannabinoids, Δ9-Tetrahydrocannibinol, Cannabidiol and Cannabinol. Vol. 168. Springer Berlin, Heidelberg, Germany: 657 pp
    1. Hylden J.L., Wilcox G.L. 1980. Intrathecal morphine in mice: a new technique. Eur. J. Pharmacol. 67:313–316 10.1016/0014-2999(80)90515-4
    1. Izzo A.A., Borrelli F., Capasso R., Di Marzo V., Mechoulam R. 2009. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 30:515–527 10.1016/j.tips.2009.07.006
    1. Liu Z.W., Xu Y., Saladino A.C., Wymore T., Tang P. 2004. Parametrization of 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane) and hexafluoroethane for nonbonded interactions. J. Phys. Chem. A. 108:781–786 10.1021/jp0368482
    1. Lynch J.W. 2004. Molecular structure and function of the glycine receptor chloride channel. Physiol. Rev. 84:1051–1095 10.1152/physrev.00042.2003
    1. Lynch J.W., Callister R.J. 2006. Glycine receptors: a new therapeutic target in pain pathways. Curr. Opin. Investig. Drugs. 7:48–53
    1. Lynch M.E., Campbell F. 2011. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br. J. Clin. Pharmacol. 72:735–744 10.1111/j.1365-2125.2011.03970.x
    1. Ma D., Liu Z., Li L., Tang P., Xu Y. 2005. Structure and dynamics of the second and third transmembrane domains of human glycine receptor. Biochemistry. 44:8790–8800 10.1021/bi050256n
    1. Manzke T., Niebert M., Koch U.R., Caley A., Vogelgesang S., Hülsmann S., Ponimaskin E., Müller U., Smart T.G., Harvey R.J., Richter D.W. 2010. Serotonin receptor 1A-modulated phosphorylation of glycine receptor α3 controls breathing in mice. J. Clin. Invest. 120:4118–4128 10.1172/JCI43029
    1. Marchand F., Perretti M., McMahon S.B. 2005. Role of the immune system in chronic pain. Nat. Rev. Neurosci. 6:521–532 10.1038/nrn1700
    1. Mogil J.S. 2009. Animal models of pain: progress and challenges. Nat. Rev. Neurosci. 10:283–294 10.1038/nrn2606
    1. Møller C., Plesset M.S. 1934. Note on an approximation treatment for many-electron systems. Physical Review. 46:618–622 10.1103/PhysRev.46.618
    1. Morris G.M., Goodsell D.S., Halliday R.S., Huey R., Hart W.E., Belew R.K., Olson A.J. 1998. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem. 19:1639–1662 10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>;2-B
    1. Murray R.M., Morrison P.D., Henquet C., Di Forti M. 2007. Cannabis, the mind and society: the hash realities. Nat. Rev. Neurosci. 8:885–895 10.1038/nrn2253
    1. Nurmikko T.J., Serpell M.G., Hoggart B., Toomey P.J., Morlion B.J., Haines D. 2007. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain. 133:210–220 10.1016/j.pain.2007.08.028
    1. Pan Y.Z., Pan H.L. 2004. Primary afferent stimulation differentially potentiates excitatory and inhibitory inputs to spinal lamina II outer and inner neurons. J. Neurophysiol. 91:2413–2421 10.1152/jn.01242.2003
    1. Patapoutian A., Tate S., Woolf C.J. 2009. Transient receptor potential channels: targeting pain at the source. Nat. Rev. Drug Discov. 8:55–68 10.1038/nrd2757
    1. Pernía-Andrade A.J., Kato A., Witschi R., Nyilas R., Katona I., Freund T.F., Watanabe M., Filitz J., Koppert W., Schüttler J., et al. 2009. Spinal endocannabinoids and CB1 receptors mediate C-fiber-induced heterosynaptic pain sensitization. Science. 325:760–764 10.1126/science.1171870
    1. Phillips J.C., Braun R., Wang W., Gumbart J., Tajkhorshid E., Villa E., Chipot C., Skeel R.D., Kalé L., Schulten K. 2005. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26:1781–1802 10.1002/jcc.20289
    1. Saladino A.C., Tang P. 2004. Optimization of structures and LJ parameters of 1-chloro-1,2,2-trifluorocyclobutane and 1,2-dichlorohexafluorocyclobutane. J. Phys. Chem. A. 108:10560–10564 10.1021/jp046662i
    1. Turcotte D., Le Dorze J.A., Esfahani F., Frost E., Gomori A., Namaka M. 2010. Examining the roles of cannabinoids in pain and other therapeutic indications: a review. Expert Opin. Pharmacother. 11:17–31 10.1517/14656560903413534
    1. Vanegas H., Schaible H.G. 2001. Prostaglandins and cyclooxygenases [correction of cycloxygenases] in the spinal cord. Prog. Neurobiol. 64:327–363 10.1016/S0301-0082(00)00063-0
    1. Vanommeslaeghe K., Hatcher E., Acharya C., Kundu S., Zhong S., Shim J., Darian E., Guvench O., Lopes P., Vorobyov I., Mackerell A.D., Jr 2010. CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J. Comput. Chem. 31:671–690
    1. Xiong W., Hosoi M., Koo B.N., Zhang L. 2008. Anandamide inhibition of 5-HT3A receptors varies with receptor density and desensitization. Mol. Pharmacol. 73:314–322 10.1124/mol.107.039149
    1. Xiong W., Cheng K., Cui T., Godlewski G., Rice K.C., Xu Y., Zhang L. 2011. Cannabinoid potentiation of glycine receptors contributes to cannabis-induced analgesia. Nat. Chem. Biol. 7:296–303 10.1038/nchembio.552
    1. Xiong W., Wu X., Lovinger D.M., Zhang L. 2012. A common molecular basis for exogenous and endogenous cannabinoid potentiation of glycine receptors. J. Neurosci. 32:5200–5208 10.1523/JNEUROSCI.6347-11.2012
    1. Yang Z., Aubrey K.R., Alroy I., Harvey R.J., Vandenberg R.J., Lynch J.W. 2008. Subunit-specific modulation of glycine receptors by cannabinoids and N-arachidonyl-glycine. Biochem. Pharmacol. 76:1014–1023 10.1016/j.bcp.2008.07.037
    1. Yevenes G.E., Zeilhofer H.U. 2011a. Allosteric modulation of glycine receptors. Br. J. Pharmacol. 164:224–236 10.1111/j.1476-5381.2011.01471.x
    1. Yévenes G.E., Zeilhofer H.U. 2011b. Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids. PLoS ONE. 6:e23886 10.1371/journal.pone.0023886
    1. Zeilhofer H.U. 2005. The glycinergic control of spinal pain processing. Cell. Mol. Life Sci. 62:2027–2035 10.1007/s00018-005-5107-2
    1. Zeilhofer H.U., Benke D., Yevenes G.E. 2012. Chronic pain States: pharmacological strategies to restore diminished inhibitory spinal pain control. Annu. Rev. Pharmacol. Toxicol. 52:111–133 10.1146/annurev-pharmtox-010611-134636
    1. Zhang G., Chen W., Lao L., Marvizón J.C. 2010. Cannabinoid CB1 receptor facilitation of substance P release in the rat spinal cord, measured as neurokinin 1 receptor internalization. Eur. J. Neurosci. 31:225–237 10.1111/j.1460-9568.2009.07075.x
    1. Zhou H.Y., Zhang H.M., Chen S.R., Pan H.L. 2008. Increased C-fiber nociceptive input potentiates inhibitory glycinergic transmission in the spinal dorsal horn. J. Pharmacol. Exp. Ther. 324:1000–1010 10.1124/jpet.107.133470
    1. Zhuo M. 2007. Neuronal mechanism for neuropathic pain. Mol. Pain. 3:14 10.1186/1744-8069-3-14
    1. Zimmer A., Zimmer A.M., Hohmann A.G., Herkenham M., Bonner T.I. 1999. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. USA. 96:5780–5785 10.1073/pnas.96.10.5780

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