Nociceptor mechanosensitivity was similarly reduced by linaclotid

Nociceptor mechanosensitivity was similarly reduced by linaclotide in response to noxious circular stretch ( Supplementary Figure 2A,B, and C). We then asked if these linaclotide-induced

anti-nociceptive effects were maintained, or indeed augmented in chronic visceral pain, such as that suffered by IBS patients.19 This question was assessed Bcl 2 inhibitor in an animal model of chronic visceral pain, where colonic nociceptor mechanical hypersensitivity23 and colonic mechanical hyperalgesia and allodynia are evident long after resolution of TNBS-induced colitis.31 and 32 We found that colonic nociceptors in the CVH model displayed pronounced mechanical hypersensitivity and that linaclotide significantly reduced their mechanosensitivity (Figure 1Bi and Bii), showing significant

reductions at 30 nM and reversing the chronic visceral mechanical hypersensitivity, with a maximal reduction of 63% at 1000 nM ( Figure 1Bi and Bii). Linaclotide’s inhibitory effect was greatly enhanced in CVH compared with healthy nociceptors ( Figure 1C). In order to determine whether these anti-nociceptive effects were specific to linaclotide or could be induced by other GC-C agonists, we also studied the endogenous hormone uroguanylin. Application of uroguanylin to the colonic mucosal surface caused significant, dose-dependent inhibition of healthy colonic nociceptors (Figure 1Di and Dii). This effect was greatly enhanced in CVH ( Figure 1Ei, Eii, and F). Overall, these findings indicate the GC-C agonists linaclotide and uroguanylin are able to inhibit colonic nociceptor function and reverse CVH. Because linaclotide inhibits colonic nociceptors, selleck kinase inhibitor as shown here, and inhibits pain responses in vivo,11 we hypothesized this inhibition should correspondingly reduce signaling of noxious CRD within the spinal cord in vivo. We identified activated neurons in the dorsal horn (DH) of the thoracolumbar spinal cord in response to Ergoloid noxious CRD by pERK immunoreactivity (IR).26 In healthy mice, intra-colonic administration of 1000 nM linaclotide resulted in significantly fewer

pERK-IR DH neurons in the thoracolumbar spinal cord after noxious CRD compared with saline administration (Figure 2A, D, and E). In response to noxious CRD, CVH mice displayed greater numbers of pERK-IR DH neurons than healthy mice, which corresponds with the extent of colonic nociceptor mechanical hypersensitivity observed in vitro. In CVH mice, linaclotide pretreatment resulted in a dramatic reduction in the number of pERK-IR DH neurons in the thoracolumbar spinal cord after noxious CRD (Figure 2B, D, and F). Overall, these results suggest that linaclotide reduces nociceptive signaling and reverses chronic visceral mechanical hypersensitivity in vivo. This finding correlates with our in vitro nociceptor findings and potentially explains improvements in abdominal pain in our IBS-C clinical trial analysis.

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