Pure Δ⁹-tetrahydrocannabivarin and a Cannabis sativa extract with high content in Δ⁹-tetrahydrocannabivarin inhibit nitrite production in murine peritoneal macrophages

Historical and scientific evidence suggests that Cannabis use has immunomodulatory and anti-inflammatory effects. We have here investigated the effect of the non-psychotropic phytocannabinoid Δ⁹-tetrahydrocannabivarin (THCV) and of a Cannabis sativa extract with high (64.8%) content in THCV (THCV-BDS) on nitric oxide (NO) production, and on cannabinoid and transient receptor potential (TRP) channel expression in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. THCV-BDS and THCV exhibited similar affinity in radioligand binding assays for CB₁ and CB₂ receptors, and inhibited, via CB₂ but not CB₁ cannabinoid receptors, nitrite production evoked by LPS in peritoneal macrophages. THCV down-regulated the over-expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin 1β (IL-1β) proteins induced by LPS. Furthermore, THCV counteracted LPS-induced up-regulation of CB₁ receptors, without affecting the changes in CB₂, TRPV2 or TRPV4 mRNA expression caused by LPS. Other TRP channels, namely, TRPA1, TRPV1, TRPV3 and TRPM8 were poorly expressed or undetectable in both unstimulated and LPS-challenged macrophages. It is concluded that THCV − via CB₂ receptor activation − inhibits nitrite production in macrophages. The effect of this phytocannabinoid was associated with a down-regulation of CB₁, but not CB₂ or TRP channel mRNA expression.