Estrogen Amplifies Pain Responses to Uterine Cervical Distension in Rats by Altering Transient Receptor Potential-1 Function

Department of Anesthesiology, Wake Forest University, Winston-Salem, North Carolina, United States
Anesthesia and analgesia (Impact Factor: 3.47). 06/2007; 104(5):1246-50, tables of contents. DOI: 10.1213/01.ane.0000263270.39480.a2
Source: PubMed


Estrogen sensitizes responses to painful stimuli, but its contribution to acute and chronic pain from the uterine cervix is unknown. Previous studies link the excitatory transient receptor potiential-1 channel (TRPV-1) to sensitization in viscera, and show that estrogen increases TRPV-1 expression in afferents from the uterine cervix. Here, we tested whether estrogen enhanced responses to uterine cervical distension in rats, and whether this involved TRPV-1 channels.
Ovariectomized rats, with or without estrogen replacement, were anesthetized and hypogastric nerve and abdominal muscle contraction reflex responses to graded uterine cervical distension were recorded. Single unit hypogastric nerve fiber firing was measured before and after acute treatment with the TRPV-1 antagonist, capsaizepine, or vehicle.
Abdominal muscle contraction reflex responses to uterine cervical distension were enhanced in estrogen-treated rats. Hypogastric afferent responses to cervical distension were reduced by capsaizepine in estrogen-treated animals, but were unaffected in ovariectomized animals without estrogen replacement.
These data suggest that the TRPV-1 channel is unimportant for normal mechanosensation in the cervix in the absence of estrogen, since capsaizepine failed to reduce responses to uterine cervical distension in rats without estrogen replacement. In contrast, TRPV-1 function is important for estrogen-induced sensitization. These data raise the possibility that acute and chronic pain coming from the cervix, such as labor or cancer, may be enhanced by estrogen and might be reduced by antagonists of TRPV-1.

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    • "The gender association for females and capsaicin response is a well-known finding in adults.5,11,12,13,14,15 Mechanistically, estrogen hormone is suggested as a link24 as it experimentally enhances the capsaicin sensing cough receptor, transient receptor potential vanilloid 1 (TRPV1).25,26 Capsaicin cough sensitivity is proven to be up-regulated among females after puberty.27 "
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    ABSTRACT: Purpose The present study aimed to examine the age and gender distributions among chronic cough patients referred to a tertiary cough clinic in Korea, and to investigate clinical factors related to the demographic findings. Methods Study participants were unselectively recruited from adult chronic cough patients who attended the cough clinic for the first time during one year. To validate their representativeness, their age and gender distributions were compared to the entire chronic cough population, or with those presenting with other chronic disease. Data from the baseline investigations were analyzed to identify clinical factors related to the demographic findings. Results A total of 272 chronic cough patients were included. They had a middle-aged female predominant feature (mean age: 52.8±15.7 years and female 69.1%). Their age and gender distributions were almost identical to the entire chronic cough population, but were distinct from patients with hypertension. Among clinical factors, the older female predominance was associated with enhanced capsaicin cough sensitivity, and also with the presence of 'cough by cold air' symptom. Allotussia and laryngeal paresthesia were highly common in chronic cough patients, affecting 94.8% and 86.8% of them, respectively. Conclusions The present study demonstrated older female predominance among adult chronic cough patients attending a referral cough clinic in Korea. The demographic features were significantly associated with the capsaicin cough responses and also potentially with allotussia (particularly cold air as the trigger). These findings suggest a role of cough reflex sensitization in the pathophysiology of chronic cough in adults.
    Allergy, asthma & immunology research 09/2014; 6(5):401-8. DOI:10.4168/aair.2014.6.5.401 · 2.43 Impact Factor
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    • "One mechanistic explanation may be the estrogen-TRPV1 association [72]. Female sex hormones have been implicated in the pathogenesis of various diseases involving ion channels, such as drug-induced arrhythmias or pain [73, 74]. In cough challenge tests, gender differences in cough sensitivity are not observed during prepuberty [75], but become evident after puberty [76] or being older [29]. "
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    ABSTRACT: Chronic cough is a common reason for patients to seek medication attention. Over the last few decades, we have experienced significant clinical success by applying the paradigm of 'evaluating and treating the causes for chronic cough'. However, we still ask ourselves 'what underlies chronic cough. Indeed in a considerable proportion of patients cough is idiopathic, or unexplained despite vigorous evaluation. Commonly associated conditions such as rhinitis, eosinophilic bronchitis, asthma, or gastroesophageal acidic reflux may not be fundamental to cough, and thus may be triggers rather than causes. The cardinal feature of chronic cough is persistent upregulation the cough reflex, which may be driven by complex interactions between biologic, neurologic, immunologic, genetic, comorbid, and environmental factors. We suggest the new paradigm 'cough hypersensitivity syndrome' should finally bring us further advances in understanding and management of chronic cough.
    01/2014; 4(1):3-13. DOI:10.5415/apallergy.2014.4.1.3
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    • "In a model of mechanical stimulation of the uterine-cervix in rats to emulate labor, ovariectomy decreased the visceromotor response which was reversed by E2 replacement and the response of the innervating hypogastric nerve afferents increased in OVx+E2 rats via activation of TRPV1 (Liu et al., 2005; Yan et al., 2007). Correspondingly , uterine-cervix afferent activity increased as estrogen levels increased during pregnancy (Liu et al., 2008). "
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    ABSTRACT: Women disproportionately suffer from many deep tissue pain conditions. Experimental studies show that women have lower pain thresholds, higher pain ratings and less tolerance to a range of painful stimuli. Most clinical and epidemiological reports suggest female gonadal hormones modulate pain for some, but not all, conditions. Similarly, animal studies support greater nociceptive sensitivity in females in many deep tissue pain models. Gonadal hormones modulate responses in primary afferents, dorsal horn neurons and supraspinal sites, but the direction of modulation is variable. This review will examine sex differences in deep tissue pain in humans and animals focusing on the role of gonadal hormones (mainly estradiol) as an underlying component of the modulation of pain sensitivity.
    Frontiers in Neuroendocrinology 07/2013; 34(4). DOI:10.1016/j.yfrne.2013.07.002 · 7.04 Impact Factor
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