Pain persists in mice lacking both Substance P and CGRPα signaling

• DOI: 10.7554/elife.93754.3
• Publication Date: 2025-03-18T14:51:50Z
• Authors: Donald Iain MacDo...; Monessha Jayabalan; Jonathan T Seaman; Rakshita Balaji; Alec R Nickolls; Alexander Theodor...

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