Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.

A Guide to Targeting the Endocannabinoid System in Drug Design

“…Recently developed 4-2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethylmorpholine (PrNMI) is an example of a peripherally restricted cannabinoid (PRCB). In rat model (0.25 mg/kg), it suppressed chemotherapy-induced peripheral neuropathy (CIPN) allodynia via CB1 agonism [78]. Another possible way to avoid CB1-related adverse effects is modulating CB1 allosterically which was achieved by GAT211-a new CB1 positive allosteric modulator (PAM).…”

Pretreatment with AM1241 Enhances the Analgesic Effect of Intrathecally Administrated Mesenchymal Stem Cells

“…Several articles have shown that CB2 receptors display antinociceptive effects on different models of neuropathic pain, indicating that the CB2 receptor maybe a good candidate for clinical development of treatment for neuropathic pain [32]. Cannabinoid s were highly effective in suppressing pain behaviors of chemotherapy-induced neuropathic pain; however, widespread use of cannabinoids was limited due to side effects in the central nervous system (CNS) [38]. As delivery of the TGF- β -neutralizing Ab did not reverse the antinociceptive effects of AM1241, even though administration of AM1241 increased the secretion of TGF- β 1, it is clear that the interaction between CB2 and TGF- β 1 is a complicated molecular process requiring further research.…”

Recent advances in understanding chemotherapy-induced peripheral neuropathy

“…There is increasing enthusiasm for the use of cannabinoids in the treatment of many chronic pain states. Agonism at CB1 and CB2 receptors has shown analgesia in rodent models of CIPN [129][130][131][132][133] but these findings have not translated into evidence of clinical efficacy. One published pilot study of nabiximols (THC:CBD mix) in 15 patients with CIPN 134 showed no significant improvement in pain, but a 2-point decrease over placebo was seen in five patients classified as "responders" 134 .…”