Visceral pain modulation in female primary afferent sensory neurons

Abstract

The variations in symptoms and pain perception across the menstrual cycle in a large percentage of women diagnosed with functional syndromes such as Irritable Bowel Syndrome (IBS), Painful Bladder Syndrome (PBS), and Chronic Pelvic Pain (CPP), suggests the involvement of modulation of sex steroid hormones. Our recent studies have shown that estrogen modulation of visceral inputs of primary afferent nociceptors, located in the afferent primary sensory neurons of the dorsal root ganglia (DRG), accounts for the observed changes in nociception. Patients with CPP frequently experience pain from several organs. For patients with IBS, the most common co-morbid diagnoses include PBS and CPP. Pain is strongly associated with these diseases and the lack of awareness of their pathology is further illustrated by the fact that the average time between the onset of pain and the diagnosis is three to ten years. CPP patients may initially only have pain in the pelvis, but a multitude of mechanisms involving the peripheral and central nervous systems can lead to development of painful sensations in other adjacent organs; examples include lower colonic pain associated with IBS, and other viscera, such as the endometrium. In addition to the central regulation of pain, it is important to understand new pathways in which sex steroid hormones, such as estrogen, affect visceral nociception peripherally.

INTRODUCTION

A growing number of nociceptive diseases that limit normal body functions presents a major risk factor for disability. In addition, visceral pain is one of the most prevalent human health problems. Many pain-associated neurodegenerative diseases are accompanied by a declined in cognitive performance and motor skills. Cells of the affected neuronal tissues may interact in a cell-to-cell manner through the transfer of hormones, cytokines, and autacoids that are released or modified in such pathological conditions. The complex interplay between these diverse mediators, the genetic background, and environmental factors, may ultimately determine the outcome of nociceptive progression. Primary afferent neurons, otherwise known as sensory neurons, carry nerve impulses from the receptors of cutaneous and visceral sense organs for processing within the central nervous system.

Clinical studies suggest the comorbidity of functional pain syndromes such as IBS, PBS, and CPP. Persistent, episodic, or chronic visceral pain is more prevalent in females, and thus, the sites and mechanisms of pain modulation of visceral nociception is an important step in understanding the gender differences in pain perception. Our recent studies on the function of estrogen receptors (ER) in DRG neurons strongly suggest that 17β-estradiol (E2) modulates visceral pain processing peripherally [1]. Both short-term and long-term exposure to E2 significantly decreased the nociceptive signaling in viscerally-labeled DRG neurons, suggesting that estradiol may affect nociception peripherally. This review summarizes new data that helps understand the E2-mediated mechanisms that modulate visceral nociception, and could lead to the development of effective and specific therapies for functional disorders by the scientific and medical communities.

Gender differences in clinical aspects of visceral pain

Pain in general, and specifically pelvic pain, is a subjective feeling that is difficult to standardize in a mathematical fashion for scientific analysis. The etiology of pain is often not clear, as there are many symptoms of the reproductive, gastrointenstinal, musculoskeletal, neurological and psychological systems that co-occur in the same patient. Viscero-somatic and viscero-viseral hyperalgesia and allodynia result in the spread of a perception of pain from an initial site to adjacent areas [2]. The variation in pain symptoms and perception, as well as behavioral responses to pain in these patients, is poorly understood. The treating clinician is often tempted to take a unidimensional approach and focus on one organ system, ignoring the psychological and behavioral manifestations of chronic pain.

There is often no clear relationship between the severity of chronic pelvic pain and the pathology in the pelvic viscera, including the reproductive tract, urinary bladder, and colon. Studies of the sympathetic nervous system in individuals with CPP associated with gynecological diseases, painful bladder syndrome, and functional bowel disorders (such as IBS), suggest a model in which the alteration of central stress circuits may be triggered and then maintain pain and pathophysiological changes in the viscera [3]. CPP patients have significantly more depression, as well as psychological and somatic complaints; they also more often give a history of physical, sexual, or emotional abuse or trauma. Chronic pain adversely affects ones mood, social and professional life, and general well-being. These quality of life issues can affect the severity of pain, the degree of impairment as a result of the painful condition, and success of treatments to alleviate the pain.

Because of the inherent subjectivity of pain, there is a wide disparity among individuals in the way that they experience pain generated by seemingly similar stimuli. There is also tension between the subjectivity of a patient’s pain experience and the insistence of the clinician upon objective findings proportional to the patient’s complaints in order to distinguish exaggerated pain reports.

Pain accounts for nearly 20% of all primary care visits in the United States. For the last couple of decades, medical literature has carefully documents the under-treatment of all type of pain by physicians. During this period, the phenomenon of under-treated pain received almost no attention from the medical community [4]. There are two essential components to pain: discriminate and affective. There discriminative component includes the ability to identify the stimulus as originating from either somatic or visceral tissue, to determine some of the physical properties of the stimulus, and to localize it in space, time, and in intensity. The affective component is the experience which motivates escape, avoidance, and protective behaviors. All of these components of pain must be considered in any discussion of the neurophysiological basis of pain. The consideration of mechanisms of pain must also include the neural system modulating it, for it is well known that pain can be profoundly influenced by other somatic stimuli, as well as by attentional, emotion, and cognitive factors. The medical history and physical examination of a patient are crucial in evaluating a suffering patient and must address all possible system that may be involved in chronic pelvic pain, not just the reproductive system. Assessing the impact of pain on various domains of a patient’s existence has become an important focus in clinical management.

Pain is a complex and individual experience that is often difficult for patients to fully describe using a conventional clinical assessment [5]. Health-related quality of life encompasses those aspects of health and well-being valued by patients, specifically, their physical, emotional, and cognitive function, and their ability to participate in meaningful activities within their family, workplace, and community. There is concern that not enough emphasis is placed on clinical face validity (i.e. issues which are important to patients and reflect their experiences). A balance between biomedical, organ-oriented, and cognitive interpersonal approaches is most appropriate at this truly psychosomatic interface. In view of the iatrogenic component in the maintenance of functional somatic syndromes, doctor-centered interventions and close observation of the doctor–patient relationship are of particular importance.

Pelvic pain affects up to 25% of women (up to a billion worldwide) at some time during their lives and can result in dysmenorrhea, dyspareunia, menstrual irregularities, back pain, gastrointestinal and genitourinary symptoms, and reduced fecundity. The incidents of persistent visceral pain associated with disorders such as IBS, CPP, PBS, and others, is up to 2–3 times higher in women that in men, suggesting modulation by E2.

Estrogen modulation of visceral-specific DRG neurons

A large body of literature supports the idea that estrogen modulates nociceptive responses in pelvic pain syndromes; however, whether this hormone is pro- or anti-nociceptive remains unresolved. The concept that the brain and other visceral systems (i.e. gastrointestinal and genitourinary) are closely connected and that this interaction plays an important role in certain feeling states, especially in clinical presentations of chronic viscerally-associated nociceptive disorders, is widely accepted in scientific and clinical communities [3]. In women, pain symptoms and nociceptive thresholds vary with reproductive cycle and our previous data strongly suggest the role of estrogen receptors in modulating nociceptive signaling [6–8]. Moreover, our recent data that estrogen can gate primary afferent responses to modulate nociception supports the hat the peripheral central system is involved in the etiology of a wide range of functional and inflammatory gastrointestinal diseases and may potentially lead to new interventions and therapies. The DRG is an important site of visceral afferent convergence and cross-sensitization. Within the context of our hypothesis, visceral nociception and nociceptor sensitization appear to be regulated by purinergic P2X₃ and vanilloid TRPV1 receptors, and 17β-estradiol modulates DRG neurons response to ATP (P2X₃ agonist) and capsaicin (TRPV1 agonist), suggesting that visceral afferent nociceptors are modulated by estrogen in the DRG [9]. Based on our data we proposed that E2 can gate the primary afferent response to increase or decrease nociception (Fig. 1).

Figure 1.

Proposed mechanism of 17-β estradiol (E2) effect on ATP-induced [Ca²⁺]_i signaling in primary sensory neurons. ATP released by tissue acts on P2X₃ receptor and capsaicin (CAP) act on vanilloid (TRPV 1) receptors resulting in activation of the L-type voltage-gated calcium channel (VGCC). ERα activates signaling cascades resulting in decreased the conductance of the L-type voltage-gated calcium channels (VGCC) by modulating nociception. E2 can act through direct DNA activation or through the membrane-associated receptors (alternative action).

Significance and Discussion

Nociceptive responses are highly complex, involving a vast array of messenger molecules interacting with enzymes and receptors of virtually every class, directing the recruitment of many types of cells to recover the healthy state, a balance between the messengers with the inherent redundancy of the different body systems makes therapeutic intervention a considerable challenge.

The localization of ER in DRG neurons and the attenuation of ATP/capsaicin- induce [Ca²⁺]_i strongly suggests that E2 modulates visceral pain processing peripherally [10]. 17-β estradiol (E2), the most common form of estrogen, acts on functional properties of P2X₃ and TRPV1 receptors in DRG neurons. Experimental long-term (chronic) exposure to E2 on sensory neurons can mimic the temporal pattern of circulating E2 levels in cycling female rodents, which is equivalent to E2 primal action on animal reproductive behavior. Cells of the affected tissues may interact in a cell-to-cell manner through the transfer of hormones, cytokines, and autacoids such as histamine, serotonin, kinins and prostaglandins that are released in pathological processes. The complex interplay and balance between these diverse mediators, aging, genetic background, and environmental factors may ultimately determine the outcome of the progression of chronic nociception. On a molecular level, these responses are highly complex, involving a vast array of messenger molecules interacting with enzymes and receptors of virtually every class, directing recruitment of many types of cells to recover a healthy state. Indeed, a balance between the messengers with the inherent redundancy of the different body systems makes therapeutic intervention a considerable challenge.

CONCLUSION

The impact on society of a successful translation of basic or clinical observations into new therapies is substantial when taking into consideration the rapid growth of scientific knowledge. Today, understanding and meeting public concerns is as important for an investigator as conducting research studies. Sex steroid hormones are thought of as indispensable cornerstones of normal function and development, but it appears that no body region, neuronal circuit, nor cell, is unaffected by them. Estrogen can affect nociception and many other systems; thus, increasing awareness of these hormones appears to be crucial. New data on understanding the mechanisms of estrogen modulation of visceral pain will hopefully lead to the development of effective, gender-specific therapies for functional disorders.