Abstract
Although endocannabinoids constitute one of the first lines of defense against pain, the anatomical locus and the precise receptor mechanisms underlying cannabinergic modulation of pain are uncertain. Clinical exploitation of the system is severely hindered by the cognitive deficits, memory impairment, motor disturbances and psychotropic effects resulting from the central actions of cannabinoids. We deleted the type 1 cannabinoid receptor (CB1) specifically in nociceptive neurons localized in the peripheral nervous system of mice, preserving its expression in the CNS, and analyzed these genetically modified mice in preclinical models of inflammatory and neuropathic pain. The nociceptor-specific loss of CB1 substantially reduced the analgesia produced by local and systemic, but not intrathecal, delivery of cannabinoids. We conclude that the contribution of CB1-type receptors expressed on the peripheral terminals of nociceptors to cannabinoid-induced analgesia is paramount, which should enable the development of peripherally acting CB1 analgesic agonists without any central side effects.
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Acknowledgements
The authors are grateful towards H.-J. Wrede and J. Harvey-White for expert technical assistance and towards S. Offermanns for comments on an earlier version of this manuscript. This work was supported by an Emmy Noether Program grant and a Klinische Forschergruppe 107 grant from the Deutsche Forschungsgemeinschaft (DFG) to R.K., a DFG grant to B.L., US National Institutes of Health (NIH) grants NS039518 and NS 038253 to C.J.W. and DA11322 and DA00286 to K.M., an Intramural Research Program grant of NIH to P.P. and G.K., and a P18444 grant from the Fonds zur Förderung der Wissenschaftlichen Forschung to M.K.
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Supplementary information
Supplementary Fig. 1
Normal development of acute and pathological pain in SNS-Cre mice as compared with wild-type littermates. (PDF 80 kb)
Supplementary Fig. 2
Effects of WIN 55,212-2 (WIN), applied via intraplantar route of administration on inflammation-induced mechanical hypersensitivity in CB1−/− mice and their wild-type littermates. (PDF 66 kb)
Supplementary Fig. 3
Analysis of SNS-CB1−/− mice and CB1fl/fl mice in the spared nerve injury (SNI) model for neuropathic pain. (PDF 70 kb)
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Agarwal, N., Pacher, P., Tegeder, I. et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci 10, 870–879 (2007). https://doi.org/10.1038/nn1916
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DOI: https://doi.org/10.1038/nn1916
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