LINACLOTIDE TREATMENT REDUCES ENDOMETRIOSIS-ASSOCIATED VAGINAL HYPERALGESIA AND MECHANICAL ALLODYNIA THROUGH VISCERO-VISCERAL CROSS-TALK

Background and aims: Endometriosis, an estrogen-dependent chronic inflammatory disease, is the most common cause of chronic pelvic pain (CPP). Here we investigated the effects of linaclotide, an FDA approved treatment for constipation-predominant IBS, in a rat model of endometriosis. Methods: Uterine horn tissue was transplanted into the mesentery of female Sprague-Dawley rats, and endometrial lesions developed eight weeks after surgery. Retrograde tracing was performed to label afferent neurons and central terminals of ileal, colonic and vaginal afferents. Guanylate cyclase-C (GC-C) mRNA expression was determined by quantitative RT-PCR and in situ hybridization.Results: Daily oral administration of linaclotide, a peripherally restricted GC-C agonist peptide acting locally within the gastrointestinal tract, increased pain thresholds to vaginal distension and mechanical hindpaw withdrawal thresholds relative to vehicle treatment. 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 via shared nerve pathways between these organs.Conclusions: Linaclotide may offer a novel therapeutic option not only for treatment of chronic endometriosis-associated pain, but concurrent treatment of comorbid CPP syndromes.