Linaclotide treatment reduces endometriosis-associated vaginal hyperalgesia and mechanical allodynia through viscerovisceral cross-talk

Ge P, Pei Ge, Ren J, JingMei Ren, Andrea M. Harrington, Luke Grundy, Joel Castro, Stuart M. Brierley, Hannig G, Gerhard Hannig
Pain · 2019 · vol. 160(11) , pp. 2566–2579 · doi:10.1097/j.pain.0000000000001657 · PMID:31335750 · W2963832375
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Linaclotide treatment reversed endometriosis-induced vaginal hyperalgesia and mechanical allodynia in rats, indicating potential therapeutic benefits for endometriosis-associated pain via viscerovisceral cross-talk.

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Abstract

Endometriosis, an estrogen-dependent chronic inflammatory disease, is the most common cause of chronic pelvic pain. Here, we investigated the effects of linaclotide, a Food and Drug Administration-approved treatment for IBS-C, in a rat model of endometriosis. Eight weeks after endometrium transplantation into the intestinal mesentery, rats developed endometrial lesions as well as vaginal hyperalgesia to distension and decreased mechanical hind paw withdrawal thresholds. Daily oral administration of linaclotide, a peripherally restricted guanylate cyclase-C (GC-C) agonist peptide acting locally within the gastrointestinal tract, increased pain thresholds to vaginal distension and mechanical hind paw withdrawal thresholds relative to vehicle treatment. Furthermore, using a cross-over design, administering linaclotide to rats previously administered vehicle resulted in increased hind paw withdrawal thresholds, whereas replacing linaclotide with vehicle treatment decreased hind paw withdrawal thresholds. Retrograde tracing of sensory afferent nerves from the ileum, colon, and vagina revealed that central terminals of these afferents lie in close apposition to one another within the dorsal horn of the spinal cord. We also identified dichotomizing dual-labelled ileal/colon innervating afferents as well as colon/vaginal dual-labelled neurons and a rare population of triple traced ileal/colon/vaginal neurons within thoracolumbar DRG. These observations provide potential sources of cross-organ interaction at the level of the DRG and spinal cord. GC-C expression is absent in the vagina and endometrial cysts suggesting that the actions of linaclotide are shared through nerve pathways between these organs. In summary, linaclotide may offer a novel therapeutic option not only for treatment of chronic endometriosis-associated pain, but also for concurrent treatment of comorbid chronic pelvic pain syndromes.

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Condition tags

endometriosischronic_pelvic_pain

MeSH descriptors

Endometriosis Hyperalgesia Pain Peptides Afferent Pathways Afferent Pathways Afferent Pathways Afferent Pathways Animals Animals Endometriosis Endometriosis Endometriosis Female Female Hyperalgesia Hyperalgesia Hyperalgesia Pain Pain

Citation neighborhood (2-hop)

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. Outer rings show 2-hop neighbours — papers reached through the immediate citers/citees. [ collapse to 1-hop ]

References (61)

Cited by (20)

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