Transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 contribute to the progression of colonic inflammation in dextran sulfate sodium-induced colitis in mice: Links to calcitonin gene-related peptide and substance P

Transient receptor potential (TRP) vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1), which are non-selective cation channels, play important roles in the sensation of pain. This study investigated the roles of TRPV1 and TRPA1 in dextran sulfate sodium (DSS)-induced murine colitis. DSS (2%) administered for 7 days caused severe colitis that was significantly less severe in TRPV1-deficient (TRPV1KO) and TRPA1-deficient (TRPA1KO) mice than that in wild-type (WT) mice. Similar colitis attenuations were observed in TRPV1KO and TRPA1KO mice but not in WT mice that had been transplanted with bone marrow cells from WT, TRPA1KO, or TRPV1KO mice. DSS treatment upregulated calcitonin gene-relative peptide (CGRP)- and substance P (SP)-positive nerve fibers in the colonic mucosa of WT mice. TRPV1KO and TRPA1KO mice showed significant reductions in the DSS-induced upregulation of SP, but the DSS-induced upregulation of CGRP was not reduced. Sensory deafferentation evoked by pretreatment with high doses of capsaicin markedly exacerbated DSS-induced colitis with reductions in DSS-induced upregulation of SP- and CGRP-positive nerve fibers. These findings suggest that neuronal TRPV1 and TRPA1 contribute to the progression of colonic inflammation. While these responses may be mediated by the upregulation of SP-mediated deleterious mechanisms, CGRP may be associated with protective mechanisms.     

Bronchoconstrictor and hypotensive effects in relation to pharmacokinetics of tachykinins in the guinea-pig —evidence for extraneuronal cleavage of neuropeptide K to neurokinin A

Summary 1. The biological effects of the tachykinins substance P (SP), neurokinin A (NKA) and neuropeptide K (NPK) were studied in relation to their pharmacokinetic properties in the guinea-pig in vivo. 2. NKA and NPK exerted a considerably larger bronchoconstrictor effect than SP. The effect of NPK was slow in onset and had a long duration. The three tachykinins showed similar hypotensive effects although NPK had a longer duration of action than SP and NKA. 3. The disappearance of NPK-like immunoreactivity (-LI) from plasma after i. v. infusion of synthetic NPK was biphasic with apparent half-lives of 0.9 min and 6 min. The plasma half-life of NKA-LI was less than 2 min, while plasma SP-LI was degraded before biochemical analysis could be performed. 4. In guinea-pig plasma at 37°C in vitro, NKA- and NPK-LI were stable for 10 min, while SP-LI disappeared with a half-life of 10 s. 5. Reversed phase HPLC analysis of plasma collected after an i. v. infusion of NPK for 25 min, indicated a partial cleavage of NPK into NKA. 6. It is concluded that potency of the biological effects of SP, NKA and NPK in the guinea-pig in vivo, may not only be attributed to activation of multiple tachykinin receptors but must also be related to the marked differences in pharmacokinetical properties between the tachykinins. Furthermore, whereas SP is rapidly degraded in plasma, NKA and NPK seem to be metabolized in other compartments. Send offprint requests to C.-R. Martling at the above address