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.
Highlights
Pain is a major cause of poor quality of life among human immunodeficiency virus (HIV) infected patients (Larue et al, 1997)
Mice treated with ddC developed thermal hyperalgesia on day 6 after treatment, i.e., reduction in reaction latency compared to the baseline latency and vehicle-treated mice (7.3 ± 0.5 s compared to 12.7 ± 0.9 s and 12.8 ± 1.0 s, respectively; n = 18 for both vehicle- and ddC-treated mice; p < 0.001 for both comparisons; Figure 1)
Treatment with ddC significantly increased the transcripts of Plcβ1 (p = 0.0021), decreased the transcripts of Daglβ (p = 0.0406), but did not significantly affect the expression of Daglα and N-arachidonoyl ethanolamine-specific phospholipase D (Napepld) (p > 0.05) in the paw skin compared to vehicle treatment (Figure 2A)
Summary
Pain is a major cause of poor quality of life among human immunodeficiency virus (HIV) infected patients (Larue et al, 1997). Some of the symptoms of neuropathic pain include hyperalgesia (an increased response to normally painful stimuli), allodynia (pain triggered by normally nonpainful stimuli, such as cloth rubbing against the skin) and spontaneous sensations such as burning, shooting, numbness, spasm and prickling (Dworkin et al, 2003; Cherry et al, 2012) It affects the feet, hands and face, it can make the performance of day to day tasks such as cooking and other physical tasks very difficult (Hitchcock et al, 2008). Nucleoside reverse transcriptase inhibitors (NRTIs) are the cornerstone of the antiretroviral therapy for human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) 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
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