Pain persists in mice lacking both Substance P and CGRPα signaling

Abstract

SummaryThe 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 generatedTac1andCalcadouble 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.

Intestinal barrier function in the naked mole-rat: an emergent model for gastrointestinal insights

“…However, it should be noted that the lack of substance P and CGRP alone cannot completely explain the lack of pain-and itch-associated behaviours induced by these compounds, as Tac1-Calca double knockout mice (therefore lacking both substance P and CGRP peptides) display intact responses to mechanical, thermal, chemical, visceral pain, itch, and neurogenic inflammation (85). In the present study, we showed that despite the virtually complete absence of ion secretion induced by histamine and capsaicin in NMRs, these animals display intestinal basal levels of substance P comparable to mice.…”

“…Finally, the lack of cutaneous neuropeptides and unusual connectivity of cutaneous afferent neurons in the spinal cord in NMRs have been proposed to explain the absence capsaicin-induced nocifensive behaviour and associated thermal hypersensitivity ( 83 ), as well as the lack of histamine-induced scratching behaviour ( 84 ) in these animals. However, it should be noted that the lack of substance P and CGRP alone cannot completely explain the lack of pain- and itch-associated behaviours induced by these compounds, as Tac1 - Calca double knockout mice (therefore lacking both substance P and CGRP peptides) display intact responses to mechanical, thermal, chemical, visceral pain, itch, and neurogenic inflammation ( 85 ). In the present study, we showed that despite the virtually complete absence of ion secretion induced by histamine and capsaicin in NMRs, these animals display intestinal basal levels of substance P comparable to mice.…”