doi: 10.1124/jpet.124.002190.
KLS-13019, a Novel Structural Analogue of Cannabidiol and GPR55 Receptor Antagonist, Prevents and Reverses Chemotherapy-Induced Peripheral Neuropathy in Rats
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- PMID:39134424
- PMCID: PMC11493436
- DOI: 10.1124/jpet.124.002190
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KLS-13019, a Novel Structural Analogue of Cannabidiol and GPR55 Receptor Antagonist, Prevents and Reverses Chemotherapy-Induced Peripheral Neuropathy in Rats
Michael Ippolito et al. J Pharmacol Exp Ther..
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Abstract
Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical need, and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol structural analog and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once-daily 1-mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for 1 week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7-10 in a chronic dosing paradigm, and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to prepaclitaxel injection baseline levels with both intraperitoneal and oral administration after acute dosing. In the chronic dosing paradigm, four consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control animals. Additionally, coadministration of KLS-13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain. SIGNIFICANCE STATEMENT: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect of cancer treatment with no known cure. The GPR55 antagonist KLS-13019 represents a novel class of drug for this condition that is a potent, durable inhibitor of allodynia associated with CIPN in rats in both prevention and reversal-dosing paradigms. This novel therapeutic approach addresses a critical area of unmet medical need.
Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.
Figures
Schematic representation of dosing paradigms. (A) The acute reversal-dosing paradigm consists of animals being sensitized with a course of chemotherapeutic agent on experimental days 1–4 (paclitaxel) or 1 and 4 (oxaliplatin) with therapeutic intervention on experimental day 7 followed by allodynia assessment. (B) The chronic reversal-dosing paradigm consists of animals being sensitized as in the acute paradigm, with KLS-13019 administration on experimental days 7–10 (Fig. 6, A and B), days 21–24 (Fig. 6B), or days 21–42 (Fig. 6C) followed by allodynia assessment. (C) The prevention paradigm consists of animals receiving chemotherapeutics and KLS-13019 simultaneously followed by allodynia assessment. Chemotherapeutic (orange), therapeutic intervention (blue). Created in BioRender.
Characterization of KLS-13019 in acute reversal of mechanical and cold allodynia in male rats. (A) Reversal of paclitaxel-induced CIPN by KLS-13019. Animals were sensitized for mechanical allodynia by four doses of 1 mg/kg paclitaxel on experimental days 1–4. KLS-13019 or KLS-13019 and 10 mg/kg ML193 was administered intraperitoneally at indicated doses 2 hours prior to assessing mechanical allodynia by von Frey monofilaments and the up-down method on experimental day 7. Filament force (g) at paw withdrawal was measured, and one-way ANOVA was performed to determine statistically significant differences between the treatment groups and paclitaxel alone. Data are presented as mean ± S.D.,n = 8; ****P ≤ 0.0001. (B) Reversal of oxaliplatin-induced CIPN by KLS-13019. Animals were sensitized for mechanical allodynia by two doses of 5 mg/kg oxaliplatin on experimental days 1 and 4. KLS-13019 was administered intraperitoneally at 10 mg/kg 2 hours prior to assessing mechanical allodynia by von Frey monofilaments and the up-down method on experimental day 7. Filament force (g) at paw withdrawal was measured, and an unpairedt test was performed to determine statistically significant differences between KLS-13019 treatment and oxaliplatin alone. Data are presented as mean ± S.D.,n = 8; ***P ≤ 0.0001. (C) Male rats were sensitized for cold allodynia by four doses of 1 mg/kg paclitaxel on experimental days 1–4. KLS-13019 was administered intraperitoneally at 10 mg/kg 2 hours prior to assessing cold allodynia by dry ice exposure on experimental day 7. Time (seconds) at paw withdrawal was measured, and an unpairedt test was performed to determine statistically significant differences between KLS-13019 treatment and paclitaxel alone. Data are presented as mean ± S.D.,n = 8; ****P ≤ 0.0001. (D) Evaluation of duration of effect of KLS-13019 after final dose. Male rats were sensitized for mechanical allodynia by four doses of 1 mg/kg paclitaxel on experimental days 1–4. KLS-13019 was administered intraperitoneally at indicated doses 2 hours prior to assessing mechanical allodynia by von Frey monofilaments and the up-down method on experimental day 7 (day 0). Filament force (g) at paw withdrawal was measured on experimental days 8–11 (days 1–4 post final injection), and two-way ANOVA was performed to determine statistically significant differences between the treatment groups and paclitaxel alone. Data are presented as mean ± S.D.,n = 8; *P ≤ 0.05. Prechemotherapy baseline average force at paw withdrawal (log g) or time to response (log s) indicated by dashed line,n = 8.
KLS-13019 administered by oral gavage dose-dependently reverses mechanical allodynia in male and female rats. Male and female rats were sensitized for mechanical allodynia by four doses of 1 mg/kg paclitaxel on experimental days 1–4. KLS-13019 was administered by oral gavage at indicated doses 2 hours prior to assessing mechanical allodynia by von Frey monofilaments and the up-down method on experimental day 7. Filament force (g) at paw withdrawal was measured, and two-way ANOVA was performed to determine statistically significant differences between the treatment groups and paclitaxel alone. Data are presented as mean ± S.D.,n = 8; *P ≤ 0.001; ***P between 0.001 and 0.0001; ****P ≤ 0.0001. Prechemotherapy baseline average force at paw withdrawal (log g) or indicated by dashed line,n = 8.
KLS-13019 does not substitute for morphine or reduce rates of lever pressing in a drug discrimination task. Discriminative stimulus and rate-decreasing effects of morphine KLS-13019 in rats trained to discriminate 3.2 mg/kg morphine from saline. (A) Percentage of total responses made on the morphine-appropriate lever. (B) Rates of responding during the 15-minute test period calculated as responses per second. Each data point is the average of one test in 5–7 rats. One-way ANOVA was performed to determine statistically significant differences between the treatment groups. Data are presented as mean ± S.D.,n = 8; **P ≤ 0.001; ****P ≤ 0.0001.
Analysis of acute reversal of mechanical allodynia by drug class. Animals were sensitized for mechanical allodynia by four doses of 1 mg/kg paclitaxel on experimental days 1–4. Various drugs were administered at indicated doses 2 hours prior to assessing mechanical allodynia by von Frey monofilaments and the up-down method on experimental day 7. The drugs tested represent different classes of CIPN therapeutics: cyan, KLS-13019; (A) green, phytocannabinoids; (B) red, morphine; (C) blue, nonopioid clinically used therapeutics; and (D) yellow, experimental GPR55-targeted molecules. Filament force (g) at paw withdrawal was measured, and one-way ANOVA was performed to determine statistically significant differences between the treatment groups and paclitaxel alone. Data are presented as mean ± S.D.,n = 8; **P ≤ 0.001; ****P ≤ 0.0001. Prechemotherapy baseline average force at paw withdrawal (log g) or indicated by dashed line,n = 8.
Chronic administration of KLS-13019 permanently reverses allodynic phenotype when administered proximally to chemotherapy. (A) Reversal of paclitaxel-induced CIPN by repeated doses of KLS-13019 in male rats. Animals were sensitized for mechanical allodynia by four doses of 1 mg/kg paclitaxel on experimental days 1–4. KLS-13019, CBD, or morphine was administered (KLS and CBD intraperitoneally, morphine subcutaneously) at indicated doses 15 minutes (morphine) or 2 hours (KLS and CBD) prior to assessing mechanical allodynia by von Frey monofilaments and the up-down method on experimental days 7–10 (assessment days 1–4) with no further intervention. Filament force (g) at paw withdrawal was measured through assessment day 42, and a mixed-effects ANOVA was performed to determine statistically significant differences between the treatment groups and paclitaxel alone. Data are presented as mean ± S.D.,n = 8; *P ≤ 0.05. (B) Reversal of paclitaxel-induced CIPN by repeated doses of KLS-13019 in female rats. Animals were sensitized for mechanical allodynia by four doses of 1 mg/kg paclitaxel on experimental days 1–4. KLS-13019 was administered at 10 mg/kg 2 hours prior to assessing mechanical allodynia by von Frey monofilaments and the up-down method on experimental days 7–10 (assessment days 1–4, cyan) or days 21–24 (assessment days 14–17, red) with no further intervention. Filament force (g) at paw withdrawal was measured through day 42, and a mixed-effects ANOVA was performed to determine statistically significant differences between the treatment windows. Data are presented as mean ± S.D.,n = 8; *P ≤ 0.05. (C) Reversal of paclitaxel-induced CIPN by repeated doses of KLS-13019 in male rats. Animals were sensitized for mechanical allodynia by four doses of 1 mg/kg paclitaxel on experimental days 1–4. KLS-13019 or morphine was administered (KLS intraperitoneally, morphine subcutaneously) at indicated doses 15 minutes (morphine) or 2 hours (KLS) prior to assessing mechanical allodynia by von Frey monofilaments and the up-down method on experimental days 21–42 (assessment days 1–21). The vehicle control and KLS cohorts did not receive further intervention. The morphine cohort received 10 mg/kg KLS on assessment days 28 and 35. Filament force (g) at paw withdrawal was measured through treatment day 35, and a mixed-effects ANOVA was performed to determine statistically significant differences between the treatment groups and paclitaxel alone. Data are presented as mean ± S.D.,n = 8; *P ≤ 0.05. Prechemotherapy baseline average force at paw withdrawal (log g) or indicated by dashed line,n = 8.
Coadministration of KLS-13019 and chemotherapy prevents allodynic phenotype from developing. Prevention of paclitaxel-induced CIPN coadministration of KLS-13019 in male rats. Animals were sensitized for mechanical allodynia by four doses of 1 mg/kg paclitaxel or paclitaxel and 10 mg/kg KLS-13019 on experimental days 1–4. Mechanical allodynia was assessed by von Frey monofilaments and the up-down method weekly from assessment day 0 to 42. Filament force (g) at paw withdrawal was measured, and a mixed-effects ANOVA was performed to determine statistically significant differences between the treatment group and paclitaxel alone. Data are presented as mean ± S.D.,n = 8; *P ≤ 0.05. Prechemotherapy baseline average force at paw withdrawal (log g) or indicated by dashed line,n = 8.
References
- Armin S, Muenster S, Abood M, Benamar K (2021) GPR55 in the brain and chronic neuropathic pain. Behav Brain Res 406:113248. - PubMed
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