title: Cannabinoid 1 receptor knockout mice display cold allodynia, but enhanced recovery from spared-nerve injury-induced mechanical hypersensitivity.
abstract: BACKGROUND
  The function of the Cannabinoid 1 receptor (CB1R) in the development of neuropathic pain is not clear. Mounting evidence suggest that CB1R expression and activation may contribute to pain. Cannabinoid 1 receptor knockout mice (CB1R-/-) generated on a C57Bl/6 background exhibit hypoalgesia in the hotplate assay and formalin test. These findings suggest that Cannabinoid 1 receptor expression mediates the responses to at least some types of painful stimuli. By using this mouse line, we sought to determine if the lack of Cannabinoid 1 receptor unveils a general hypoalgesic phenotype, including protection against the development of neuropathic pain. The acetone test was used to measure cold sensitivity, the electronic von Frey was used to measure mechanical thresholds before and after spared-nerve injury, and analysis of footprint patterns was conducted to determine if motor function is differentially affected after nerve-injury in mice with varying levels of Cannabinoid 1 receptor.
  
  
  RESULTS
  At baseline, CB1R-/- mice were hypersensitive in the acetone test, and this phenotype was maintained after spared-nerve injury. Using calcium imaging of lumbar dorsal root ganglion (DRG) cultures, a higher percentage of neurons isolated from CB1R-/- mice were menthol sensitive relative to DRG isolated from wild-type (CB1R+/+) mice. Baseline mechanical thresholds did not differ among genotypes, and mechanical hypersensitivity developed similarly in the first two weeks following spared-nerve injury (SNI). At two weeks post-SNI, CB1R-/- mice recovered significantly from mechanical hypersensitivity, while the CB1R+/+ mice did not. Heterozygous knockouts (CB1R+/-) transiently developed cold allodynia only after injury, but recovered mechanical thresholds to a similar extent as the CB1R-/- mice. Sciatic functional indices, which reflect overall nerve health, and alternation coefficients, which indicate uniformity of strides, were not significantly different among genotypes.
  
  
  CONCLUSIONS
  Cold allodynia and significant recovery from spared-nerve injury-induced mechanical hypersensitivity are two novel phenotypes which characterize the global CB1R-/- mice. An increase in transient receptor potential channel of melastatin 8 channel function in DRG neurons may underlie the cold phenotype. Recovery of mechanical thresholds in the CB1R knockouts was independent of motor function. These results indicate that CB1R expression contributes to the development of persistent mechanical hypersensitivity, protects against the development of robust cold allodynia but is not involved in motor impairment following spared-nerve injury in mice.
authors.affiliation: Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Langone Medical Center, NY, USA alexandra.sideris@nyumc.org.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sideris
authors.affiliation: Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Langone Medical Center, NY, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Piskoun
authors.affiliation: Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Langone Medical Center, NY, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Russo
authors.affiliation: Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Langone Medical Center, NY, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Norcini
authors.affiliation: Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Langone Medical Center, NY, USA Department of Physiology and Neuroscience, NYU Langone Medical Center, NY, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Blanck
authors.affiliation: Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Langone Medical Center, NY, USA Department of Biochemistry & Molecular Pharmacology, NYU Langone Medical Center, NY, USA.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Recio-Pinto
mesh_terms: D000818:Animals; D003080:Cold Temperature; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D008610:Menthol / Q000494:pharmacology; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency* / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries* / Q000503:physiopathology*
chemical_list: D043884:Receptor, Cannabinoid, CB1; D008610:Menthol
keywords: CB1R knockout; Cannabinoid 1 receptor; allodynia; dorsal root ganglion; neuropathic pain; spared-nerve injury