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 two peptides. Finally, neuropathic pain evoked by nerve injury or chemotherapy treatment was also preserved in peptide-deficient mice. Thus, our results demonstrate that even in combination, Substance P and CGRPα are not required for the transmission of acute and chronic pain.

Neural activity in auditory cortex tracks the amplitude-onset envelope of continuous speech, but recent work counterintuitively suggests that neural tracking increases when speech is masked by background noise, despite reduced speech intelligibility. Noise-related amplification could indicate that stochastic resonance – the response facilitation through noise – supports neural speech tracking, but a comprehensive account is lacking. In five human electroencephalography experiments, the current study demonstrates a generalized enhancement of neural speech tracking due to minimal background noise. Results show that (1) neural speech tracking is enhanced for speech masked by background noise at very high signal-to-noise ratios (~30 dB SNR) where speech is highly intelligible; (2) this enhancement is independent of attention; (3) it generalizes across different stationary background maskers, but is strongest for 12-talker babble; and (4) it is present for headphone and free-field listening, suggesting that the neural-tracking enhancement generalizes to real-life listening. The work paints a clear picture that minimal background noise enhances the neural representation of the speech onset-envelope, suggesting that stochastic resonance contributes to neural speech tracking. The work further highlights non-linearities of neural tracking induced by background noise that make its use as a biological marker for speech processing challenging.