Slowly Signaling G Protein–Biased CB2 Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence

Abstract

The CB cannabinoid agonist LY2828360 lacked both toxicity and efficacy in a clinical trial for osteoarthritis. Whether LY2828360 suppresses neuropathic pain has not been reported, and its signaling profile is unknown. In vitro, LY2828360 was a slowly acting but efficacious G protein-biased CB agonist, inhibiting cAMP accumulation and activating extracellular signal-regulated kinase 1/2 signaling while failing to recruit arrestin, activate inositol phosphate signaling, or internalize CB2 receptors. In wild-type (WT) mice, LY2828360 (3 mg/kg per day i.p. × 12 days) suppressed chemotherapy-induced neuropathic pain produced by paclitaxel without producing tolerance. Antiallodynic efficacy of LY2828360 was absent in CB knockout (KO) mice. Morphine (10 mg/kg per day i.p. × 12 days) tolerance developed in CBKO mice but not in WT mice with a history of LY2828360 treatment (3 mg/kg per day i.p. × 12 days). LY2828360-induced antiallodynic efficacy was preserved in WT mice previously rendered tolerant to morphine (10 mg/kg per day i.p. × 12 days), but it was absent in morphine-tolerant CBKO mice. Coadministration of LY2828360 (0.1 mg/kg per day i.p. × 12 days) with morphine (10 mg/kg per day × 12 days) blocked morphine tolerance in WT but not in CBKO mice. WT mice that received LY2828360 coadministered with morphine exhibited a trend ( = 0.055) toward fewer naloxone-precipitated jumps compared with CBKO mice. In conclusion, LY2828360 is a slowly signaling, G protein-biased CB agonist that attenuates chemotherapy-induced neuropathic pain without producing tolerance and may prolong effective opioid analgesia while reducing opioid dependence. LY2828360 may be useful as a first-line treatment in chemotherapy-induced neuropathic pain and may be highly efficacious in neuropathic pain states that are refractive to opioid analgesics.

Cannabinoid CB2 Agonist AM1710 Differentially Suppresses Distinct Pathological Pain States and Attenuates Morphine Tolerance and Withdrawal

“…The duration of responding to cold (seconds) was evaluated after the assessment of responsiveness to mechanical stimulation for pain models in which cold allodynia is prominent, as we have previously published (Lin et al, 2017). A 1-ml syringe with the needle removed was filled with acetone (Sigma-Aldrich).…”

“…The treatment period was composed of two phases, phase I and phase II, with 4 days separating the two phases. The protocol used here was identical to that used in our previously published work to show that the G protein-based CB2 agonist LY2828360 suppressed paclitaxelinduced neuropathic pain and blocked development of tolerance to morphine in paclitaxel-treated mice (Lin et al, 2017). One group of mice received daily intraperitoneal injections of AM1710 for 12 consecutive days (5 mg/kg per day, i.p.)…”

“…We validated antinociceptive efficacy of AM1710 and evaluated whether AM1710 could attenuate morphine tolerance and naloxone-precipitated opioid withdrawal in paclitaxeltreated mice as reported previously for LY2828360 (Lin et al, 2017). We also evaluated whether AM1710 acts as a functional CB1 antagonist in vivo by challenging mice treated chronically with D 9 -tetrahydrocannabinol (D 9 -THC) with AM1710 or rimonabant to precipitate CB1-dependent cannabinoid withdrawal.…”

“…CB2 receptor activation does not produce unwanted CNS-mediated side effects associated with CB1 (Malan et al, 2003;Guindon and Hohmann, 2008;Deng et al, 2015b). We recently reported that the G protein-biased CB2 agonist LY2828360 (8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purine) suppressed chemotherapy-induced neuropathic pain and attenuated development of morphine tolerance and physical dependence in neuropathic mice (Lin et al, 2017). Whether such effects are specific to LY2828360 or translate more broadly to other CB2 agonists with different signaling profiles remains unknown.…”

Opioid‐sparing effects of cannabinoids on morphine analgesia: participation of CB1 and CB2 receptors

“…The development of selective CB 2 receptor agonists raises the possibility of utilizing cannabinoids devoid of psychoactive activity as analgesics. In fact, CB 2 receptor agonists given acutely or chronically have been reported to have analgesic activity against neuropathic pain in mice (Deng et al, 2015;Lin, Dhopeshwarkar, Huibregtse, Mackie, & Hohmann, 2018). Further, CB 2 receptor knockout mice have enhanced nociception in a mouse model of sciatic nerve injury (Racz et al, 2008).…”