Endocannabinoid System Attenuates Oxaliplatin-Induced Peripheral Sensory Neuropathy Through the Activation of CB1 Receptors

Abstract

Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2 mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56 days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10 mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5 mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3 mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.

Chronic Cannabigerol as an Effective Therapeutic for Cisplatin-Induced Neuropathic Pain

“…Next, we sought to identify CIPN-sensitive genes in the dorsal root ganglia (DRG) that are modified by this treatment regimen. We analyzed genes known to be targeted by cannabigerol and other cannabinoids, including Cnr1, Cnr2, Gpr55, Faah, Mgll, Adra2a-c, Pparg [15][16][17][18][19], or to have been previously published as volatile in a cisplatin-induced neuropathy setting in DRG, including Drd2, Gfap, and Oprm1 [13]. Percent differences in relative gene expression (measured by qRT-PCR) between CBG and vehicle groups and statistical significance are reported in Table 2; raw data are provided in Supplemental Data, Figures S1 and S2.…”

“…Additionally, CIPN may escalate over time without additional exposure to cisplatin, and pain persists for months to years after one's last dose of cisplatin [3]. Patients, providers, and caregivers often turn to other medications for various pain indications such as gabapentin, tricyclic antidepressants, natural products, or medicated topicals, to ameliorate the chronic and debilitating nature of the pain; however, none of these have successfully shown benefits in clinical Pharmaceuticals 2023, 16, 1442 2 of 13 trials [4]. There is growing patient and research interest in cannabinoid formulations with ∆9-tetrahydrocannabinol (THC) for pain syndromes, in part due to wide pharmacological activity with relatively limited side effects.…”

The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 Inhibition

“…In seeking more effective innovative therapies, one should take into account the endocannabinoid system, a key regulator of chronic pain, especially through modulation of its main receptors, CB1 and CB2 [ 2 , 3 ]. Even though CB1 stimulation induced analgesia in several painful states [ 4 , 5 , 6 , 7 ], CB1 agonists are not ideal pain-relieving agents for clinical use due to their serious side effects, such as addiction, excessive sedation, fatigue, and dizziness [ 8 , 9 ]. Thus, the alternative of using CB2 receptor modulators could be a therapeutic advantage, as they lack the negative neurological effects induced by CB1 receptor modulation.…”

Effect of the Cannabinoid Agonist WIN 55,212-2 on Neuropathic and Visceral Pain Induced by a Non-Diarrheagenic Dose of the Antitumoral Drug 5-Fluorouracil in the Rat

“…In a previous work performed in rats, the non-selective cannabinoid agonist WIN 55,212-2 (WIN) at a non-psychotropic dose partly attenuated 5-FU-induced diarrhea, but did not counteract the associated mucositis [30]. Interestingly, this and other cannabinoids may improve peripheral tactile neuropathy induced by different antitumoral drugs in rodents, including cisplatin, paclitaxel, vincristine and oxaliplatin [31][32][33][34][35][36][37]. However, their effects on the alterations of somatic and visceral sensitivity that 5-FU may cause have not yet been studied.…”