Vitamin B5 is a context-dependent dietary regulator of nociception.

Abstract

Chronic pain has an enormous impact on the quality of life of billions of patients, families, and caregivers worldwide. Current therapies do not adequately address pain for most patients. A basic understanding of the conserved genetic framework controlling pain may help us develop better, non-addictive pain therapies. Here we identify new conserved and druggable analgesic targets using tissue-specific functional genomic screening of candidate "pain" genes in the fly. From these efforts we describe 23 new pain genes for further consideration. This included Acsl, a fatty acid-metabolizing enzyme and mammalian orthologs are involved in arachidonic acid metabolism. Acsl knockdown and mutant larvae showed delayed nocifensive responses to localized and global noxious heat. Mechanistically, knockdown of Acsl reduced dendritic branching of nociceptive neurons. Surprisingly, the pain phenotype in these animals could be rescued through dietary intervention with vitamin B5, highlighting the interplay between genetics, metabolism and nutrient environment to establish sensory perception thresholds. Together, our functional genomic screening within the sensory nociceptor has identified new nociception genes that provide a better understanding of pain biology and can help guide the development of new painkillers.