Pain persists in mice lacking both Substance P and CGRPα signaling

The neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides and their receptors are expressed at high levels in pain-responsive neurons from the periphery to the brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve pain in clinical trials. Since Substance P and CGRPα are extensively co-expressed we hypothesized that their simultaneous inhibition would be required for effective analgesia. We therefore generated Tac1 and Calca double knockout (DKO) mice and assessed their behavior using a wide range of pain-relevant assays. As expected, Substance P and CGRPα peptides were undetectable throughout the nervous system of DKO mice. To our surprise, these animals displayed largely intact responses to mechanical, thermal, chemical, and visceral pain stimuli, as well as itch. Moreover, chronic inflammatory pain and neurogenic inflammation were unaffected by loss of the t..., , , # Pain persists in mice lacking both Substance P and CGRPα signaling

[https://doi.org/10.5061/dryad.hqbzkh1tm](https://doi.org/10.5061/dryad.hqbzkh1tm)

## Description of the data and file structure

These files encompass the source data for the manuscript. Each workbook contains sheets for each figure panel, including figure supplements. Units and variables are described within the sheets and in the manuscript. cap-Capsaicin, SP-Substance P, veh-Vehicle

**FIG 1 – excel file reporting source data for Figure 1 and associated supplements.**

These data report the results of neuropeptide sniffer imaging experiments performed in Wild type- WT and Calca double knockout (DKO) mice. All values are reported as Delta F/F0 (quantification of changes in fluorescence). Experimental conditions are different chemical stimuli, and where concentrations are reported, these are in Molar.

**FIG 2 – excel file reporting source data for Figure 2 and associated supplements.**

These data report the result...,