It is possible that this is caused by the binding of ACEA to CB2

It is possible that this is caused by the binding of ACEA to CB2 receptors at micromolar concentrations (Ki of 3 ± 1 μm; Hillard et al., 1999). There is evidence for the expression of CB2 receptors in neurons and glia throughout selleck the CNS (Gong et al., 2006), including

in the spinal cord and primary afferents (Beltramo et al., 2006). ACEA is also a TRPV1 agonist at micromolar concentrations (Price et al., 2004). However, opening of TRPV1 channels by ACEA would further increase substance P release (Marvizon et al., 2003a), so this could not explain the reversal of the increase in NK1R internalization at high concentrations of ACEA. Our results are at variance with those of Lever & Malcangio (2002), who found that capsaicin-induced substance P release from mouse spinal cord slices was considerably increased by the CB1 antagonist rimonabant and inhibited by the endocannabinoid anandamide. Epigenetic inhibitor nmr However, they used rimonabant at a dose, 5 μm, at which it may activate other receptors such as adenosine A1 receptors (Savinainen et al., 2003). We found that the inhibition of NK1R internalization produced by rimonabant and AM281 disappeared at micromolar doses.

As for anandamide, its inhibition could have been mediated by receptors other than CB1 that also bind anandamide, such as CB2 receptors (Devane et al., 1992; Kano et al., 2009) and TRPV1 (Zygmunt et al., 1999; Starowicz et al., 2007). AM251 is also an agonist of the novel cannabinoid receptor GPR55 (Ryberg et al., 2007;

Kano et al., 2009). However, its inhibition of substance P this website release cannot be attributed to this receptor for various reasons. First, unlike AM251, the GPR55 agonist O-1640 (Johns et al., 2007; Oka et al., 2007; Waldeck-Weiermair et al., 2008) did not inhibit NK1R internalization evoked by dorsal root stimulation (Fig. 2B). Second, like AM251, rimonabant (which acts as an antagonist of GPR55; Ross, 2009) inhibited NK1R internalization. Third, AM281, which is ineffective at GPR55 (Ross, 2009), also inhibited NK1R internalization. TRPV1 channels are activated by some endocannabinoids (Kano et al., 2009). However, the effects of the synthetic cannabinoids used in this study cannot be attributed to TRVP1 either, because NK1R internalization induced by direct application of capsaicin to the slices was not inhibited by AM251 (Fig. 6B). We have previously shown (Lao et al., 2003) that capsaicin-induced substance P release bypasses the inhibition produced by GABAB receptors and probably other GPCRs. This is because GPCRs inhibit substance P release by inactivating voltage-dependent Ca2+ channels (Strock & Diverse-Pierluissi, 2004; Raingo et al., 2007), whereas TRPV1 channels provide an alternative route for Ca2+ entry into the terminal that bypasses the voltage-dependent Ca2+ channels. The inhibition of substance P release by the CB1 antagonists AM251, AM281and rimonabant is probably caused by blockade of the effect of endocannabinoids released in the dorsal horn.

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