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

Abstract

AM1710 (3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c) chromen-6-one), a cannabilactone cannabinoid receptor 2 (CB2) agonist, suppresses chemotherapy-induced neuropathic pain in rodents without producing tolerance or unwanted side effects associated with CB1 receptors; however, the signaling profile of AM1710 remains incompletely characterized. It is not known whether AM1710 behaves as a broadspectrum analgesic and/or suppresses the development of opioid tolerance and physical dependence. In vitro, AM1710 inhibited forskolin-stimulated cAMP production and produced enduring activation of extracellular signal-regulated kinases 1/2 phosphorylation in human embryonic kidney (HEK) cells stably expressing mCB2. Only modest species differences in the signaling profile of AM1710 were observed between HEK cells stably expressing mCB2 and hCB2. In vivo, AM1710 produced a sustained inhibition of paclitaxel-induced allodynia in mice. In paclitaxel-treated mice, a history of AM1710 treatment (5 mg/kg per day  12 day, i.p.) delayed the development of antinociceptive tolerance to morphine and attenuated morphine-induced physical dependence. AM1710 (10 mg/kg, i.p.) did not precipitate CB1 receptor-mediated withdrawal in mice rendered tolerant to D 9 -tetrahydrocannabinol, suggesting that AM1710 is not a functional CB1 antagonist in vivo. Furthermore, AM1710 (1, 3, 10 mg/kg, i.p.) did not suppress established mechanical allodynia induced by complete Freund's adjuvant (CFA) or by partial sciatic nerve ligation (PSNL). Similarly, prophylactic and chronic dosing with AM1710 (10 mg/kg, i.p.) did not produce antiallodynic efficacy in the CFA model. By contrast, gabapentin suppressed allodynia in both CFA and PSNL models. Our results indicate that AM1710 is not a broad-spectrum analgesic agent in mice and suggest the need to identify signaling pathways underlying CB2 therapeutic efficacy to identify appropriate indications for clinical translation.

Cannabinoid Receptor 2 (CB2) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes

“…Although in some systems gallein may inhibit GRK2 and possibly associated arrestin signaling 73 , we do not know of any studies suggesting that PTX blocks arrestin-initiated signaling other than one report of a small potency shift for arrestin recruitment 74 . Interestingly NF023, which we confirmed in cAMP assays inhibits Gαi, did not block the p-ERK response, indicating that this blocker specifically inhibits Gα subunits without influencing Gβγ activity as also observed previously 75 In contrast with prior studies in human promyelocytic leukemia HL60 cells 25 and CB2overexpressing HEK cells 24 we did not observe JNK phosphorylation. However, we note that activation of this pathway may be cell-context dependent given that in LPS-stimulated human monocytes JNK was inhibited by a CB2 ligand 12 .…”

“…Akt kinase (protein kinase B), an important mediator of immunomodulation reviewed in 19 can be activated 20 , inhibited 21 , or unaffected 22 by CB2 activation. A stress-activated protein kinase JNK (c-Jun NH2-terminal -5 -kinase), involved in pro-inflammatory signaling reviewed in 23 , has been shown to be activated 24,25 and inhibited 12 via CB2.…”

Challenges and Opportunities in Preclinical Research of Synthetic Cannabinoids for Pain Therapy

“…Via precise interaction of cannabinoid receptors, the peripheral administration of synthetic cannabinoids reduces the formalin pain response (a model of inflammatory pain). The mechanism does not appear to be completely elucidated but may be based on a reduced release of peripheral neuron neuropeptides or by modulating the primary afferent sensitization of other types of molecules [74].…”

Synthesis of Functionalized Cannabilactones

“…Two first-generation cannabilactone analogs, namely AM1710 and AM1714 (1a and 1b, Figure 1), exhibited potent peripheral analgesic activity in several animal models of inflammatory and neuropathic pain [16,18,19]. Additionally, AM1710 was found to suppress chemotherapy-induced neuropathic pain and delay the development of antinociceptive tolerance to morphine in rodents [20]. The cannabilactone template has some structural similarities with the psychoactive cannabis constituent (−)-∆ 9 /∆ 8 -tetrahydrocannabinol (THC, 2a, Figure 1).…”