CB₁ Knockout Mice Unveil Sustained CB₂-Mediated Antiallodynic Effects of the Mixed CB₁/CB₂ Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain

Abstract

Cannabinoids suppress neuropathic pain through activation of cannabinoid CB 1 and/or CB 2 receptors; however, unwanted CB 1 -mediated cannabimimetic effects limit clinical use. We asked whether CP55,940 [(2)-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-(3-hydroxypropyl)cyclohexanol], a potent cannabinoid that binds with similar affinity to CB 1 and CB 2 in vitro, produces functionally separable CB 1 -and CB 2 -mediated pharmacological effects in vivo. We evaluated antiallodynic effects, possible tolerance, and cannabimimetic effects (e.g., hypothermia, catalepsy, CB 1 -dependent withdrawal signs) after systemic CP55,940 treatment in a mouse model of toxic neuropathy produced by a chemotherapeutic agent, paclitaxel. The contribution of CB 1 and CB 2 receptors to in vivo actions of CP55,940 was evaluated using CB 1 knockout (KO), CB 2 KO, and wild-type (WT) mice. Low-dose CP55,940 (0.3 mg/kg daily, i.p. ) suppressed paclitaxel-induced allodynia in WT and CB 2 KO mice, but not CB 1 KO mice. Low-dose CP55,940 also produced hypothermia and rimonabantprecipitated withdrawal in WT, but not CB 1 KO, mice. In WT mice, tolerance developed to CB 1 -mediated hypothermic effects of CP55,940 earlier than to antiallodynic effects. High-dose CP55,940 (10 mg/kg daily, i.p.) produced catalepsy in WT mice, which precluded determination of antiallodynic efficacy but produced sustained CB 2 -mediated suppression of paclitaxelinduced allodynia in CB 1 KO mice; these antiallodynic effects were blocked by the CB 2 antagonist 6-iodopravadoline (AM630). Highdose CP55,940 did not produce hypothermia or rimonabantprecipitated withdrawal in CB 1 KO mice. Our results using the mixed CB 1 /CB 2 agonist CP55,940 document that CB 1 and CB 2 receptor activations produce mechanistically distinct suppression of neuropathic pain. Our study highlights the therapeutic potential of targeting cannabinoid CB 2 receptors to bypass unwanted central effects associated with CB 1 receptor activation.

Behavioral Characterization of κ Opioid Receptor Agonist Spiradoline and Cannabinoid Receptor Agonist CP55940 Mixtures in Rats

“…CP55940 alone and spiradoline alone dose dependently increased tail withdrawal latency (antinociception), decreased body temperature (hypothermia), and decreased responding for food, and these results were consistent with previous studies (Leander, 1983;Brandt and France, 1996;Mello and Negus, 1998;Smith et al, 2003;Terner et al, 2003;De Vry and Jentzsch, 2004;Craft et al, 2012;Deng et al, 2015). Hypothermic effects have been reported for the k opioid receptor agonists U50488, U69593, and salvinorin A (Hayes et al, 1985;Cavicchini et al, 1989;Nemmani et al, 2001;Baker and Meert, 2002), and there is a report of spiradoline producing hypothermia after intracerebroventricular administration (Adler and Geller, 1993).…”

Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence

“…Challenge with a CB1 antagonist increases withdrawal-like behaviors (i.e. paw tremors/flutters and/or headshakes) in mice treated chronically with orthosteric CB1 agonists (present study and see (6, 7, 47)) and the MGL inhibitor JZL184 (13, 14) but not in mice treated chronically with the CB1 PAM GAT211. In our study, rimonabant challenge increased somatic withdrawal behaviors (i.e.…”

“…Moreover, GAT211 did not elicit cardinal signs of CB1 activation or produce physical dependence. Therapeutic efficacy was maintained over 19 days of repeated dosing, suggesting possible superiority of CB1 PAMs as an analgesic strategy over either orthosteric CB1 agonists (see also(6, 7)) or MGL inhibitors. By contrast, tolerance develops rapidly to CB1 agonists(6) and high dose MGL inhibitors(13, 14).…”

“…anandamide, 2-arachidonoylglycerol (2-AG)) and enzymes that catalyze endocannabinoid synthesis and degradation(1). Cannabinoid agonists such as Δ 9 -tetrahydrocannabinol (Δ 9 -THC) suppress pathological pain in preclinical studies(2-4) but also produce unwanted psychotropic effects that limit therapeutic use(5-7). Inhibitors of fatty-acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), the major enzymes degrading anandamide and 2-AG, respectively, suppress pain in rodent models of traumatic nerve injury, toxic neuropathy(8, 9) and hyperglycemia(10) with efficacy comparable to or surpassing conventional treatments(9).…”

Neurotoxicity to DRG neurons varies between rodent strains treated with cisplatin and bortezomib

“…Rodents of different species or strains have been used extensively to study CIPN in vivo and in vitro , with little attention to strain differences. Transgenic mice are important tools for determining the role of a gene in CIPN mechanism [20]. Rats are good models for the study of nerve conduction velocities and behavior in relation to CIPN [21].…”