Optimization of capsaicin‐induced dermal blood flow measurement by laser Doppler imaging in cynomolgus macaque

Abstract

Peripheral application of capsaicin, a chemical irritant, can stimulate the transient receptor potential vanilloid 1 (TRPV1) at nerve endings and cause calcitonin gene-related peptide (CGRP) release, which in turn mediates an increase in blood flow. 1 Furthermore, CGRP release in the trigeminovascular system has been established as one of the key mediators in migraine pathophysiology. 2,3 Being a potent vasodilator of cranial blood vessels, CGRP has become an engagement target in migraine therapeutics. 4 Based on these physiological mechanisms, capsaicin-induced dermal blood flow (CIDBF) has been tested in non-human primate (NHP) as an animal model for the evaluation of anti-migraine therapeutics. [5][6][7] This involves topical capsaicin to produce an increase in dermal blood flow (DBF), which is measured using laser Doppler imaging (LDI). 5 The effectiveness of anti-migraine treatments is evaluated based on their ability to block CGRP release and thereby reduce CIDBF. 4 Although the NHP CIDBF model has been established, 5 there are multiple factors that can vary DBF measurements and thus experimental reproducibility. Desensitization to capsaicin is one of the concerns that can contribute largely to variations in DBF. While mechanisms of desensitization of nerve fibers are not entirely understood, repeated capsaicin exposure can result in a period of refractoriness in which the nerve becomes irresponsive toward capsaicin or even other stimuli. [8][9][10] In humans, it has been reported that frequent applications of capsaicin for extended periods could diminish vasodilation. 9,11 Consequence of desensitization can be detrimental to reproducibility depending on the study design. CIDBF