Spinal and peripheral analgesic effects of the CB₂ cannabinoid receptor agonist AM1241 in two models of bone cancer‐induced pain

Abstract

Background and purpose:The activation of CB2 receptors induces analgesia in experimental models of chronic pain. The present experiments were designed to study whether the activation of peripheral or spinal CB2 receptors relieves thermal hyperalgesia and mechanical allodynia in two models of bone cancer pain. Experimental approach: NCTC 2472 osteosarcoma or B16-F10 melanoma cells were intratibially inoculated to C3H/He and C57BL/6 mice. Thermal hyperalgesia was assessed by the unilateral hot plate test and mechanical allodynia by the von Frey test. AM1241 (CB2 receptor agonist), AM251 (CB1 receptor antagonist), SR144528 (CB2 receptor antagonist) and naloxone were used. CB2 receptor expression was measured by Western blot. ) abolished thermal hyperalgesia and mechanical allodynia in both tumour models. The antihyperalgesic effect was antagonized by subcutaneous, intrathecal or peri-tumour administration of SR144528. In contrast, the antiallodynic effect was inhibited by systemic or intrathecal, but not peri-tumour, injection of SR144528. The effects of AM1241 were unchanged by AM251 but were prevented by naloxone. No change in CB2 receptor expression was found in spinal cord or dorsal root ganglia. Conclusions and implications: Spinal CB2 receptors are involved in the antiallodynic effect induced by AM1241 in two neoplastic models while peripheral and spinal receptors participate in the antihyperalgesic effects. Both effects were mediated by endogenous opiates. The use of drugs that activate CB2 receptors could be a useful strategy to counteract bone cancer-induced pain symptoms.

Dynamic changes to the endocannabinoid system in models of chronic pain

“…Despite these differences, administration of cannabinoid agonists produces robust analgesia in all models of cancer pain via activation of both CB1 [46,50,60] and CB2 receptors [46][47][48][49][50]. Interestingly, antinociceptive effects of both intrathecal and systemic administration of the CB2 receptor selective agonist AM1241 were abolished by intrathecal administration of the CB2 receptor antagonist SR144528, indicating a spinal site of action [48], and the effects of systemic AM1241 were blocked by naloxone [48], indicating a role of endogenous opioids, which warrants further investigation. Such interactions have previously been demonstrated in keratinocytes in naive rats [61], and may indicate interplay between the endogenous nociceptive systems at multiple levels of the pain pathways.…”

“…Studies in models of cancer pain have revealed differing effects on the expression of cannabinoid receptors within the CNS, with some groups reporting an upregulation of CB1 receptor in the L5 DRG in mice injected with squamous cell carcinoma into the hindpaw [46], while others studying models of bone cancer report no change in expression [48,60]. Despite these differences, administration of cannabinoid agonists produces robust analgesia in all models of cancer pain via activation of both CB1 [46,50,60] and CB2 receptors [46][47][48][49][50]. Interestingly, antinociceptive effects of both intrathecal and systemic administration of the CB2 receptor selective agonist AM1241 were abolished by intrathecal administration of the CB2 receptor antagonist SR144528, indicating a spinal site of action [48], and the effects of systemic AM1241 were blocked by naloxone [48], indicating a role of endogenous opioids, which warrants further investigation.…”

“…Cannabinoid drugs are now used in the symptomatic treatment of pain associated with cancer [59]. Studies in models of cancer pain have revealed differing effects on the expression of cannabinoid receptors within the CNS, with some groups reporting an upregulation of CB1 receptor in the L5 DRG in mice injected with squamous cell carcinoma into the hindpaw [46], while others studying models of bone cancer report no change in expression [48,60]. Despite these differences, administration of cannabinoid agonists produces robust analgesia in all models of cancer pain via activation of both CB1 [46,50,60] and CB2 receptors [46][47][48][49][50].…”

An Inhibitor of Neuronal Exocytosis (DD04107) Displays Long-Lasting In Vivo Activity against Chronic Inflammatory and Neuropathic Pain

“…Mechanical allodynia in mice was assessed by applying von Frey filaments to the plantar side of the paws as reported previously (Curto-Reyes et al, 2010). Mice were placed on a wire-mesh platform, covered with transparent plastic containers.…”

“…Thus, thermal hyperalgesia was studied 4 weeks after the inoculation of NCTC 2472 osteosarcoma cells, whereas mechanical allodynia was assessed at week 2 (Curto-Reyes et al, 2010). DD04107 was dissolved in saline (2 mg/ml) and administered subcutaneously in a volume of 10 ml/kg 4 weeks after the inoculation of NCTC 2472 osteosarcoma cells for the thermal hyperalgesia studies and 2 weeks after the inoculation of NCTC 2472 osteosarcoma cells for the mechanical allodynia studies.…”