The Role of Calcitonin Gene-Related Peptide in the Endothelin-1 mediated Pain Perception In vessels calcitonin gene-related peptide (CGRP) has an anti-endothelinergic effect by terminating the binding between the endothelin-A (ET-A) receptor and endothelin-1 (ET-1). As ET-1 can elicit pain through ET-A receptors on nociceptors, we tested the hypothesis that CGRP might similar as in vessels promote dissociation of the ET-1/ET-A receptor complex on nociceptors. This way CGRP could have analgesic effects in the periphery. Calcitonin receptor-like receptor transgenic mice (CLR-tg) showed a significant decreased sympathetic response during thermal stimulation in etomidate anaesthesia. Baseline values of behaviourally assessed mechanical and thermal sensitivity were also decreased, but no difference was observed after induction of hyperalgesia compared to the control mice. αCGRP-knockout (αCGRP-/-) mice showed an increased nociception during thermal stimulation in etomidate anaesthesia, but no difference compared to their wild-type controls was observed for behaviourally assessed mechanical and thermal sensitivity neither during baseline conditions nor after induction of hyperalgesia. Intraplantar ET-1 injection confirmed that αCGRP-/- mice are more sensitive to this pain inducing peptide, whereas the CLR-tg mice have a decreased nociception compared to their respective controls. Our findings suggest that CGRP may have an analgesic effect on the peripheral endings of the nociceptors by modulating the interaction between ET-1 and ET-A receptors, as described in vessels.