A syngeneic inoculation mouse model of endometriosis that develops multiple comorbid visceral and cutaneous pain like behaviours

Maddern, Jessica; Grundy, Luke; Harrington, Andrea M.; Schober, Gudrun; Castro, Joel; Brierley, Stuart M.

doi:10.1097/j.pain.0000000000002552

Cited by 7 publications

(11 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We then investigated whether Tsp1a could modulate pain sensitivity evoked by vaginal distension (VD) in conscious Sham control mice. In vivo vaginal pain sensitivity was monitored by measuring the VMR to increasing VD pressures using EMG electrodes surgically implanted into the abdominal muscles as previously described [16; 17; 48]. In Sham control mice, we found that VD evoked an increase in the VMR, with the degree of VMR related to the amount of pressure applied to the vagina ( Figure 3A-B ).…”

Section: Resultsmentioning

confidence: 73%

“…Further analysis revealed the VMR to non-noxious (20–30 mmHg) ( Figure 6Cii) and noxious (40– 70 mmHg) ( Figure 6Ciii) DPs were significantly enhanced in Endo mice. Endo mice displayed both allodynia and hyperalgesia, which are hallmark signs of CPP in a wide range of inflammatory diseases, including endometriosis [6; 7; 17; 47; 48; 50; 58; 62]. We then found that Endo mice treated intravaginally with Tsp1a displayed significantly reduced VMRs evoked by VD compared with Endo mice treated intravaginally with vehicle ( Figure 7A-C ).…”

Section: Resultsmentioning

confidence: 80%

“…While changes in the expression profile of Na V 1.7 have been associated with endometriosis in these studies, the functional role of Na V 1.7 in sensing pain from pelvic organs affected by endometriosis has not yet been explored. Therefore, we investigated the role of Na V 1.7 in our established syngeneic mouse model of endometriosis [48]. We show here, for the first time, that pelvic afferents innervating the mouse vagina become hypersensitive to mechanical stimuli in endometriosis.…”

Section: Discussionmentioning

confidence: 99%

“…In this study we used a syngeneic mouse model of endometriosis, previously established and characterised by our group [48]. Briefly, female mice were ovariectomised under isoflurane and received estrogen (100 μg/kg estradiol benzoate) intraperitoneally (IP).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, female mice were ovariectomised under isoflurane and received estrogen (100 μg/kg estradiol benzoate) intraperitoneally (IP). Following ovariectomy recovery (minimum of 5 days), endometriosis (Endo) or Sham inductions were performed as previously described [48]. For this, recipient mice were anesthetized under isoflurane, and a small (0.5 cm) incision was made into the peritoneal space just below the umbilicus.…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

The voltage-gated sodium channel Na_V1.7 underlies endometriosis-associated chronic pelvic pain

Castro

Maddern

Chow

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Chronic pelvic pain (CPP) is the primary symptom of endometriosis patients, but adequate treatments are lacking. Modulation of ion channels expressed by sensory nerves innervating the viscera have shown promise for the treatment of irritable bowel syndrome and overactive bladder. However, similar therapies have not been explored for endometriosis-associated CPP. Here we examined the role of the voltage-gated sodium (NaV) channel NaV1.7 in the sensitivity of vagina-innervating sensory afferents and investigated whether NaV1.7 inhibition reduces nociceptive signals from the vagina and ameliorates endometriosis-associated CPP. The mechanical responsiveness of vagina-innervating sensory afferents was assessed with ex vivo single unit recording preparations. Pain evoked by vaginal distension (VD) was quantified by the visceromotor response (VMR) in vivo. In control mice, pharmacological activation of NaV1.7 with OD1 sensitised vagina-innervating pelvic afferents to mechanical stimuli. Using a syngeneic mouse model of endometriosis, we established that endometriosis sensitized vagina-innervating pelvic afferents to mechanical stimuli. The highly selective NaV1.7 inhibitor Tsp1a revealed that this afferent hypersensitivity occurred in a NaV1.7-dependent manner. Moreover, in vivo intra-vaginal treatment with Tsp1a reduced the exaggerated VMRs to VD that is characteristic of mice with endometriosis. Conversely, Tsp1a did not alter ex vivo afferent mechanosensitivity or in vivo VMRs to VD in Sham control mice. Collectively, these findings suggest that NaV1.7 plays a crucial role in endometriosis-induced vaginal hyperalgesia. Importantly, NaV1.7 inhibition selectively alleviated endometriosis-associated CPP without the loss of normal sensation, suggesting that selective targeting of NaV1.7 could improve the quality of life of women with endometriosis.

show abstract

Section: Resultsmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

The voltage-gated sodium channel Na_V1.7 underlies endometriosis-associated chronic pelvic pain

Castro

Maddern

Chow

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Pre-clinical Models of Endometriosis: A Focus on Chronic Pain

2023

View full text Add to dashboard Cite

Investigating endometriosis development and endometriosis-related pain over time and in relation to estrogen in a laparoscopic mouse model

Peterse,

Verhassel,

Fassbender

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: Endometriosis is a complex disease, and its pathophysiology is still unclear. Therefore, endometriosis animal models need to be carefully selected and examined to be useful for identification of novel therapies for women with endometriosis. In this study, we evaluated endometriosis-associated pain, and time- and estrogen-related development of endometriotic lesions after laparoscopic implantation of menstrual endometrium in a homologous mouse model for endometriosis. Methods: Endometriosis was induced by laparoscopic introduction of 10 menstrual endometrial tissue pieces into the peritoneum of ovariectomized recipient mice (59 estrogen-substituted; 59 estrogen-depleted). Sham animals (57 estrogen-substituted; 60 estrogen-depleted) received 10 pieces of perigonadal adipose tissue. The animals were sacrificed at 1, 2, 3, 4, 6 or 8 weeks after induction, the attached peritoneal implants localized and excised and immunohistochemically analyzed. Additionally, endometriosis-related pain was evaluated by measuring mechanical allodynia, thermal hyperalgesia, locomotor activity and anxiety-like behavior before and after tissue implantation. Results: At least one implant per mouse could be retrieved in 94% (111/118) of the endometrial tissue animals and in 78% (91/117) of the adipose tissue animals (p<0.001). Peritoneal implant take rate was significantly higher in endometrial tissue animals (2.5 +/- 1.4) compared to adipose tissue animals (1.6 +/- 1.5) (p<0.0001), regardless of estrogen supplementation and time of sacrifice. Hemosiderin could be observed more often (p<0.0001) in attached peritoneal implants of the endometrial tissue animals (67%, 68/101), compared to the adipose tissue animals (37%, 31/83). Ki67 staining showed a higher proliferation index in the attached peritoneal implants retrieved after one week, compared to the other time points of both endometrial tissue and adipose tissue animals. The behavioral test showed no significant difference in mechanical and thermal sensitivity, locomotor activity and anxiety-behavior between the menstrual endometrial tissue and adipose tissue implanted animals. Nevertheless, the estrogen-substituted animals showed decreased activity in the tests featuring thermal nociception and anxiety-like behavior, compared to the estrogen-depleted animals. Additionally, time after implantation showed to have a positive effect on thermal sensitivity, locomotor activity and anxiety-related behavior in all animals, as the mice became less sensitive to thermal stimuli, more active in the open field test and buried less marbles in the marble burying test. Conclusion: This study showed an increased attachment of menstrual endometrium compared to adipose tissue in the peritoneum when using laparoscopic induction. There was no apparent influence of estrogen on tissue attachment, proliferation or appearance. A decrease in cell proliferation in peritoneal implants occurred over time. Locomotor activity, anxiety-like behavior, and mechanical and thermal sensitivity of the animals was not affected after induction of endometriosis, regardless of the type of implanted tissue. Altogether, we showed that the current methodology used to induce endometriosis was not sufficient to develop endometriotic lesions that contained both stromal and epithelial cells. Moreover, the current methodology was not able to detect specific endometriosis-related pain.

show abstract

A syngeneic inoculation mouse model of endometriosis that develops multiple comorbid visceral and cutaneous pain like behaviours

Abstract: A mouse model of endometriosis that recapitulates clinical features and symptoms experienced by women with endometriosis, including hypersensitivity across visceral organs, skin, and altered behaviour.

Cited by 7 publications

References 57 publications

The voltage-gated sodium channel Na_V1.7 underlies endometriosis-associated chronic pelvic pain

The voltage-gated sodium channel Na_V1.7 underlies endometriosis-associated chronic pelvic pain

Pre-clinical Models of Endometriosis: A Focus on Chronic Pain

Investigating endometriosis development and endometriosis-related pain over time and in relation to estrogen in a laparoscopic mouse model

Contact Info

Product

Resources

About

A syngeneic inoculation mouse model of endometriosis that develops multiple comorbid visceral and cutaneous pain like behaviours

Abstract: A mouse model of endometriosis that recapitulates clinical features and symptoms experienced by women with endometriosis, including hypersensitivity across visceral organs, skin, and altered behaviour.

Cited by 7 publications

References 57 publications

The voltage-gated sodium channel NaV1.7 underlies endometriosis-associated chronic pelvic pain

The voltage-gated sodium channel NaV1.7 underlies endometriosis-associated chronic pelvic pain

Pre-clinical Models of Endometriosis: A Focus on Chronic Pain

Investigating endometriosis development and endometriosis-related pain over time and in relation to estrogen in a laparoscopic mouse model

Contact Info

Product

Resources

About

The voltage-gated sodium channel Na_V1.7 underlies endometriosis-associated chronic pelvic pain

The voltage-gated sodium channel Na_V1.7 underlies endometriosis-associated chronic pelvic pain