Article

Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors

Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 05/2012; 209(6):1121-34. DOI: 10.1084/jem.20120242
Source: PubMed

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.

3 Followers
 · 
187 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The gate control theory of pain proposes that inhibitory neurons of the spinal dorsal horn exert critical control over the relay of nociceptive signals to higher brain areas. Here we investigated how the glycinergic subpopulation of these neurons contributes to modality-specific pain and itch processing. We generated a GlyT2::Cre transgenic mouse line suitable for virus-mediated retrograde tracing studies and for spatially precise ablation, silencing, and activation of glycinergic neurons. We found that these neurons receive sensory input mainly from myelinated primary sensory neurons and that their local toxin-mediated ablation or silencing induces localized mechanical, heat, and cold hyperalgesia; spontaneous flinching behavior; and excessive licking and biting directed toward the corresponding skin territory. Conversely, local pharmacogenetic activation of the same neurons alleviated neuropathic hyperalgesia and chloroquine- and histamine-induced itch. These results establish glycinergic neurons of the spinal dorsal horn as key elements of an inhibitory pain and itch control circuit. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Neuron 03/2015; 85(6). DOI:10.1016/j.neuron.2015.02.028 · 15.98 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a chronic pelvic pain condition largely refractory to treatment. Cannabis (marijuana) use has been reported for a wide variety of chronic pain conditions, but no study has examined prevalence of cannabis use, symptom benefit or side effects, or frequency in CP/CPPS. Participants were recruited from an outpatient CP/CPPS urology clinic (n = 98) and online through the Prostatitis Foundation website (n = 244). Participants completed questionnaires (demographics, CP/CPPS, depression, cannabis). The clinic sample included Canadian patients and the online sample included primarily American patients. Due to differences, groups were examined separately. Almost 50% of respondents reported using cannabis (clinic n = 49; online n = 89). Of the cannabis users, 36.8% of clinic and 75% of online respondents reported that it improved their symptoms. Most of the respondents (from the clinic and online groups) reported that cannabis improved their mood, pain, muscle spasms, and sleep. However, they did not note any improvements for weakness, fatigue, numbness, ambulation, and urination. Overall, the effectiveness of cannabis for CP/CPPS was "somewhat/very effective" (57% clinic; 63% online). There were no differences between side effects or choice of consumption and most reported using cannabis rarely. These are the first estimates in men suffering from CP/CPPS and suggest that while cannabis use is prevalent, its medical use and benefit are unknown. This is an understudied area and the benefit or hazard for cannabis use awaits further study.
    11/2014; 8(11-12):E901-5. DOI:10.5489/cuaj.2268
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glycine receptor (GlyR) chloride channels mediate fast inhibitory neurotransmission in the spinal cord and brainstem. Four GlyR subunits (α1-3, β) have been identified in humans, and their differential anatomical distributions underlie a diversity of synaptic isoforms with unique physiological and pharmacological properties. To improve our understanding of these properties, we induced the formation of recombinant synapses between cultured spinal neurons and HEK293 cells expressing GlyR subunits of interest plus the synapse-promoting molecule, neuroligin-2A. In the heterosynapses thus formed, recombinant α1β and α3β GlyRs mediated fast decaying inhibitory postsynaptic currents (IPSCs) whereas α2β GlyRs mediated slow decaying IPSCs. These results are consistent with the fragmentary information available from native synapses and single channel kinetic studies. As β subunit incorporation is considered essential for localizing GlyRs at the synapse, we were surprised that α1-3 homomers supported robust IPSCs with β subunit incorporation accelerating IPSC rise and decay times in α2β and α3β heteromers only. Finally, heterosynapses incorporating α1D80Aβ and α1A52Sβ GlyRs exhibited accelerated IPSC decay rates closely resembling those recorded in native synapses from mutant mice homozygous for these mutations, providing an additional validation of our technique. Glycinergic heterosynapses should prove useful for evaluating the effects of drugs, hereditary disease mutations or other interventions on defined GlyR subunit combinations under realistic synaptic activation conditions.
    Neuropharmacology 11/2014; 89. DOI:10.1016/j.neuropharm.2014.10.026 · 4.82 Impact Factor

Full-text (3 Sources)

Download
90 Downloads
Available from
May 23, 2014