Antihyperalgesic Activities of Endocannabinoids in a Mouse Model of Antiretroviral-Induced Neuropathic Pain

Abstract

Background: Nucleoside reverse transcriptase inhibitors (NRTIs) are the cornerstone of the antiretroviral therapy for human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). However, their use is sometimes limited by the development of a painful sensory neuropathy, which does not respond well to drugs. Smoked cannabis has been reported in clinical trials to have efficacy in relieving painful HIV-associated sensory neuropathy.Objectives: The aim of this study was to evaluate whether the expression of endocannabinoid system molecules is altered during NRTI-induced painful neuropathy, and also whether endocannabinoids can attenuate NRTI-induced painful neuropathy.Methods: BALB/c mice were treated with 25 mg/kg of 2′,3′-dideoxycytidine (ddC, zalcitabine), a NRTI, to induce thermal hyperalgesia. The expression of endocannabinoid system molecules was evaluated by real time polymerase chain reaction in the brain, spinal cord and paw skin at 6 days post ddC administration, a time point when mice had developed thermal hyperalgesia. The effects of the endocannabinoids, N-arachidonoyl ethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG), the cannabinoid type 1 (CB1) receptor antagonist AM 251, CB2 receptor antagonist AM 630, and G protein-coupled receptor 55 (GPR55) antagonists ML193 and CID 16020046 on ddC-induced thermal hyperalgesia were evaluated using the hot plate test.Results: ddC treatment resulted in thermal hyperalgesia and increased transcripts of the synthesizing enzyme Plcβ1 and decreased Daglβ in the paw skins, but not Napepld, and Daglα compared to vehicle treatment. Transcripts of the inactivating enzymes Faah and Mgll were downregulated in the brain and/or paw skin but not in the spinal cord of ddC-treated mice. Both AEA and 2-AG had antihyperalgesic effects in mice with ddC-induced thermal hyperalgesia, but had no effect in ddC-naïve mice. The antihyperalgesic activity of AEA was antagonized by AM251 and AM630, whereas the activity of 2-AG was antagonized by AM251, ML193 and CID 16020046, but not by AM630.Conclusion: These data show that ddC induces thermal hyperalgesia, which is associated with dysregulation of the mRNA expression of some endocannabinoid system molecules. The endocannabinoids AEA and 2-AG have antihyperalgesic activity, which is dependent on cannabinoid receptor and GPR55 activation. Thus, agonists of cannabinoid receptors and GPR55 could be useful therapeutic agents for the management of NRTI-induced painful sensory neuropathy.

β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain

“…The mice did not have changes in thermal hypersensitivity, similar to what was described by Wallace et al where ddC induced mechanical allodynia but did not alter the response to thermal stimuli in rats [54]. However, this is in contrast to our previous findings where a single dose of ddC induced mechanical allodynia and thermal hyperalgesia [12,50], possibly because of the difference in number of administrations and cumulative dose, i.e., five administrations with a cumulative dose of ddC of 125 mg/kg compared to a single dose of 25 mg/kg in the previous studies.…”

“…The CB1 receptor antagonist AM 251 (Tocris, Bristol, UK) and the CB2 receptor antagonist AM 630 (Tocris) were dissolved (ultrasonicated to prevent foam formation) in normal saline containing 5% Tween 80 and 5% propylene glycol and both drugs were administered i.p. at a dose of 3 mg/kg, similar to the doses used previously [12,50,78]. All the drugs were freshly prepared on the day of administration.…”

“…Thermal sensitivity was assessed using the hot or cold plate (Panlab SL, Barcelona, Spain) at 55 ± 1 • C or 4 ± 1 • C, as described before [12,92,93]. Briefly, each mouse was placed individually in a hot or cold plate, and the first sign of nociception, paw licking, flinching or jump response to avoid the heat or cold was recorded and the animal immediately removed from the plate.…”

Cannabinoids and agmatine as potential therapeutic alternatives for cisplatin-induced peripheral neuropathy

“…Cannabinoid receptor agonists have shown antinociceptive properties in a variety of NP models. They have been shown to alleviate hyperalgesia in peripheral nerve injury-induced, 51 – 60 chemotherapy-induced, 61 – 68 diabetes-induced 69 – 74 and antiretroviral-induced 75 neuropathy models. The anti-hyperalgesic effect of cannabinoids was suggested to be mediated through cannabinoid receptors, 51 , 53 , 68 , 75 – 77 interacting with spinal mGlu5 receptors, 78 5-HT1A receptors, 79 posterior inhibition of p38 MAPK/NF-κB activation and cytokine release, 68 GPR55 activation 75 and stimulating endogenous norepinephrine release.…”

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice

“…Given the expansion of the aging HIV-infected population, it is clinically important to characterize the effect of HAART components on the pathogenesis of pain and elucidate the underlying pathogenic mechanism in the context of aging. However, despite reported effects of specific NRTIs in young adult rodents (Zheng et al, 2011; Munawar et al, 2017), no studies have been carried out on aging animals.…”