Abstract
Neuropathic pain associated with nucleoside reverse transcriptase inhibitors (NRTIs), therapeutic agents for human immunodeficiency virus (HIV), responds poorly to available drugs. Smoked cannabis was reported to relieve HIV-associated neuropathic pain in clinical trials. Some constituents of cannabis (Cannabis sativa) activate cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors. However, activation of the CB1 receptor is associated with side effects such as psychosis and physical dependence. Therefore, we investigated the effect of β-caryophyllene (BCP), a CB2-selective phytocannabinoid, in a model of NRTI-induced neuropathic pain. Female BALB/c mice treated with 2′-3′-dideoxycytidine (ddC, zalcitabine), a NRTI, for 5 days developed mechanical allodynia, which was prevented by cotreatment with BCP, minocycline or pentoxifylline. A CB2 receptor antagonist (AM 630), but not a CB1 receptor antagonist (AM 251), antagonized BCP attenuation of established ddC-induced mechanical allodynia. β-Caryophyllene prevented the ddC-induced increase in cytokine (interleukin 1 beta, tumor necrosis factor alpha and interferon gamma) transcripts in the paw skin and brain, as well as the phosphorylation level of Erk1/2 in the brain. In conclusion, BCP prevents NRTI-induced mechanical allodynia, possibly via reducing the inflammatory response, and attenuates mechanical allodynia through CB2 receptor activation. Therefore, BCP could be useful for prevention and treatment of antiretroviral-induced neuropathic pain.
Highlights
Antiretroviral combination therapy is used to treat human immunodeficiency virus (HIV) infection and has resulted in the lowering of viral load, minimized viral transmission and made HIV a chronic disease rather than a fatal one [1,2]
The initial antiretroviral therapy (ART) regimen for a treatment of naïve patient generally consists of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a drug from one of three drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) [4]
Treatment with ddC significantly increased the expression of interferon gamma (Ifng) (Figure 4a,b) and interleukin-1 beta (Il1b) (Figure 4c,d) mRNA in both the paw skin and the brain compared to vehicle-only-treated control mice (p < 0.05)
Summary
Antiretroviral combination therapy is used to treat human immunodeficiency virus (HIV) infection and has resulted in the lowering of viral load, minimized viral transmission and made HIV a chronic disease rather than a fatal one [1,2]. The regular pharmacological treatments for other forms of neuropathic pain are widely used, not proven effective in patients with HIV-associated neuropathic pain These include antidepressants [22,23], anticonvulsants [24,25], topical agents, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids [6,26,27]. 8% transdermal patch [30] have proven to be effective against HIV-associated neuropathic pain in randomized clinical trials [27] Despite these findings, it is well known that cannabis (Cannabis sativa) produces psychosis as a side effect; its use is prohibited in most countries and smoking carry significant health risks [31,32]. REVIEW anti-inflammatory and antiallodynic effects against various types of neuropathic pain [46,47,48,49]. 3 of 18
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