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 … Show more
“…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.…”
Section: Gene Expression Changes From Daily Administration Of Cannabi...mentioning
confidence: 99%
“…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.…”
Cannabigerol (CBG), derived from the cannabis plant, acts as an acute analgesic in a model of cisplatin-induced peripheral neuropathy (CIPN) in mice. There are no curative, long-lasting treatments for CIPN available to humans. We investigated the ability of chronic CBG to alleviate mechanical hypersensitivity due to CIPN in mice by measuring responses to 7 and 14 days of daily CBG. We found that CBG treatment (i.p.) for 7 and 14 consecutive days significantly reduced mechanical hypersensitivity in male and female mice with CIPN and reduced pain sensitivity up to 60–70% of baseline levels (p < 0.001 for all), 24 h after the last injection. Additionally, we found that daily treatment with CBG did not evoke tolerance and did not incur significant weight change or adverse events. The efficacy of CBG was independent of the estrous cycle phase. Therefore, chronic CBG administration can provide at least 24 h of antinociceptive effect in mice. These findings support the study of CBG as a long-lasting neuropathic pain therapy, which acts without tolerance in both males and females.
“…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.…”
Section: Gene Expression Changes From Daily Administration Of Cannabi...mentioning
confidence: 99%
“…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.…”
Cannabigerol (CBG), derived from the cannabis plant, acts as an acute analgesic in a model of cisplatin-induced peripheral neuropathy (CIPN) in mice. There are no curative, long-lasting treatments for CIPN available to humans. We investigated the ability of chronic CBG to alleviate mechanical hypersensitivity due to CIPN in mice by measuring responses to 7 and 14 days of daily CBG. We found that CBG treatment (i.p.) for 7 and 14 consecutive days significantly reduced mechanical hypersensitivity in male and female mice with CIPN and reduced pain sensitivity up to 60–70% of baseline levels (p < 0.001 for all), 24 h after the last injection. Additionally, we found that daily treatment with CBG did not evoke tolerance and did not incur significant weight change or adverse events. The efficacy of CBG was independent of the estrous cycle phase. Therefore, chronic CBG administration can provide at least 24 h of antinociceptive effect in mice. These findings support the study of CBG as a long-lasting neuropathic pain therapy, which acts without tolerance in both males and females.
“…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.…”
Neuropathic pain is a chronic disabling condition with a 7–10% of prevalence in the general population that is largely undertreated. Available analgesic therapies are poorly effective and are often accompanied by numerous side effects. Growing evidence indicates cannabinoids are a valuable treatment opportunity for neuropathic pain. The endocannabinoid system is an important regulator of pain perception through the CB1 receptors, but CB1 agonists, while largely effective, are not always satisfactory pain-relieving agents in clinics because of their serious adverse effects. Recently, several CB2 agonists have shown analgesic, anti-hyperalgesic, and anti-allodynic activity in the absence of CB1-induced psychostimulant effects, offering promise in neuropathic pain management. The aim of this study was to evaluate the anti-neuropathic activity of a novel selective CB2 agonist, COR167, in a preclinical model of peripheral neuropathy, the spared nerve injury (SNI). Oral COR167, in a dose-dependent manner, attenuated mechanical allodynia and thermal hyperalgesia after acute and repeated administration, showing the absence of tolerance induction. At anti-neuropathic doses, COR167 did not show any alteration in the locomotor behavior. SNI mice showed increased microglial levels of HDAC1 protein in the ipsilateral side of the spinal cord, along with NF-kB activation. COR167 treatment prevented the HDAC1 overexpression and the NF-kB activation and increased the levels of the anti-inflammatory cytokine IL-10 through a CB2-mediated mechanism. Oral administration of COR167 shows promising therapeutic potential in the management of neuropathic pain conditions.
“…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.…”
5-fluorouracil (5-FU) is an antineoplastic drug used to treat colorectal cancer, but it causes, among other adverse effects, diarrhea and mucositis, as well as enteric neuropathy, as shown in experimental animals. It might also cause neuropathic pain and alterations in visceral sensitivity, but this has not been studied in either patients or experimental animals. Cannabinoids have antimotility and analgesic effects and may alleviate 5-FU-induced adverse effects. Our aim was to evaluate the effects of the cannabinoid agonist WIN 55,212-2 on neuropathic and visceral pain induced by a non-diarrheagenic dose of 5-FU. Male Wistar rats received a dose of 5-FU (150 mg/kg, ip) and gastrointestinal motility, colonic sensitivity, gut wall structure and tactile sensitivity were evaluated. WIN 55,212-2 (WIN) was administered to evaluate its effect on somatic (50–100 µg ipl; 1 mg/kg, ip) and visceral (1 mg/kg, ip) sensitivity. The cannabinoid tetrad was used to assess the central effects of WIN (1 mg/kg, ip). 5-FU decreased food intake and body weight gain, produced mucositis and thermal hyperalgesia, but these effects were reduced afterwards, and were not accompanied by diarrhea. Tactile mechanical allodynia was also evident and persisted for 15 days. Interestingly, it was alleviated by WIN. 5-FU tended to increase colonic sensitivity whereas WIN reduced the abdominal contractions induced by increasing intracolonic pressure in both control and 5-FU-treated animals. Importantly, the alleviating effects of WIN against those induced by 5-FU were not accompanied by any effect in the cannabinoid tetrad. The activation of the peripheral cannabinoid system may be useful to alleviate neuropathic and visceral pain associated with antitumoral treatment.
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