Abstract
BackgroundOlvanil (NE 19550) is a non-pungent synthetic analogue of capsaicin, the natural pungent ingredient of capsicum which activates the transient receptor potential vanilloid type-1 (TRPV1) channel and was developed as a potential analgesic compound. Olvanil has potent anti-hyperalgesic effects in several experimental models of chronic pain. Here we report the inhibitory effects of olvanil on nociceptive processing using cultured dorsal root ganglion (DRG) neurons and compare the effects of capsaicin and olvanil on thermal nociceptive processing in vivo; potential contributions of the cannabinoid CB1 receptor to olvanil’s anti-hyperalgesic effects were also investigated.MethodsA hot plate analgesia meter was used to evaluate the anti-nociceptive effects of olvanil on capsaicin-induced thermal hyperalgesia and the role played by CB1 receptors in mediating these effects. Single cell calcium imaging studies of DRG neurons were employed to determine the desensitizing effects of olvanil on capsaicin-evoked calcium responses. Statistical analysis used Student’s t test or one way ANOVA followed by Dunnett’s post-hoc test as appropriate.ResultsBoth olvanil (100 nM) and capsaicin (100 nM) produced significant increases in intracellular calcium concentrations [Ca2+]i in cultured DRG neurons. Olvanil was able to desensitise TRPV1 responses to further capsaicin exposure more effectively than capsaicin. Intraplantar injection of capsaicin (0.1, 0.3 and 1 μg) produced a robust TRPV1-dependant thermal hyperalgesia in rats, whilst olvanil (0.1, 0.3 and 1 μg) produced no hyperalgesia, emphasizing its lack of pungency. The highest dose of olvanil significantly reduced the hyperalgesic effects of capsaicin in vivo. Intraplantar injection of the selective cannabinoid CB1 receptor antagonist rimonabant (1 μg) altered neither capsaicin-induced thermal hyperalgesia nor the desensitizing properties of olvanil, indicating a lack of involvement of CB1 receptors.ConclusionsOlvanil is effective in reducing capsaicin-induced thermal hyperalgesia, probably via directly desensitizing TRPV1 channels in a CB1 receptor-independent fashion. The results presented clearly support the potential for olvanil in the development of new topical analgesic preparations for treating chronic pain conditions while avoiding the unwanted side effects of capsaicin treatments.
Highlights
Olvanil (NE 19550) is a non-pungent synthetic analogue of capsaicin, the natural pungent ingredient of capsicum which activates the transient receptor potential vanilloid type-1 (TRPV1) channel and was developed as a potential analgesic compound
TRPV1 is a chemically-gated non-specific cation channel with high calcium permeability [1], which integrates a range of painful stimuli including noxious heat (>43 ° C) [2] and low pH [3] and which responds to pungent compounds, such as capsaicin [2, 4]
In order to investigate whether the ability of olvanil to reduce the subsequent effects of capsaicin was due to a persistent desensitization of TRPV1, we studied the effect of repeated applications of olvanil on the dorsal root ganglion (DRG) neurons
Summary
Olvanil (NE 19550) is a non-pungent synthetic analogue of capsaicin, the natural pungent ingredient of capsicum which activates the transient receptor potential vanilloid type-1 (TRPV1) channel and was developed as a potential analgesic compound. TRPV1 (transient receptor potential vanilloid type 1) is a chemically-gated non-specific cation channel with high calcium permeability [1], which integrates a range of painful stimuli including noxious heat (>43 ° C) [2] and low pH [3] and which responds to pungent compounds, such as capsaicin [2, 4]. Elevation of [Ca2+]i through TRPV1 activation leads to desensitization of the channel, probably through calcium-dependent mechanisms including Ca2+/calmodulin and the Ca2+-sensitive phosphatase calcineurin [14, 15]. Topical preparations containing low concentrations of capsaicin have long been used as over-the-counter remedies for pain
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