Neural reorganization associated with visceral pain

Abstract

Functional pain syndromes, including such common disorders as irritable bowel syndrome (within the field of gastroenterology); chronic pelvic pain (in gynecology); interstitial cystitis/painful bladder syndrome (in urology); fibromyalgia (in rheumatology) and others cross multiple disciplines affecting more than 20% of the population worldwide and are more common in women. Inflammation is not a common pathophysiological pathway for a number of chronic (including functional) diseases. One of the possible explanations for this phenomenon is the neuronal reorganization associated with pain transmission (nociception), but the mechanisms of the crosstalk are unclear. Moreover, clinical presentations of functional syndromes often lack a specific pathology in the affected organ but may respond to a visceral cross-sensitization in which increased nociceptive input from an inflamed organ (i.e., uterus) sensitizes neurons that receive convergent input from an unaffected organ (i.e., colon or bladder). This mini-review focuses on the novel mechanisms for possible therapeutic interventions associated with the visceral pain primarily focusing on visceral nociceptors located within primary afferent neurons of dorsal root ganglia. Since there are observed gender differences in prevalence of functional diseases, it is proposed that estrogen may modulate nociceptor sensitization. Understanding these gender differences and neuronal reorganization associated with visceral pain will be the basis of translational efforts to modulate viscerally mediated mechanisms or functional disorders with ultimate goal to develop new therapies to treat functional disorders.

INTRODUCTION

Currently, more than 100 million Americans and 1.5 billion people worldwide suffer from chronic pain. This is more than cancer, diabetes, and heart diseases combined. Visceral tissues release many neuroactive substances by activating purinergic, cholinergic, serotoninergic, and other receptors on primary afferent neurons located within dorsal root ganglia (DRG). Small diameter afferent neurons function as nociceptors: the sensors of the pain pathway. Hypersensitivity associated with many diseases results from changes in tissue-neuronal communication. A functional disorder is a medical condition that impairs the normal function, but without major organic cause such as irritation or inflammation and where the organ or part of the body looks completely normal under medical examination. Chronic overlapping pain conditions (e.g., irritable bowel syndrome, temporomandibular disorder, fibromyalgia) have minimal identifiable origins in organic disease or injury and represent a highly significant pain management challenge for treating physician and patient. These disorders characterized by severe visceral pain are 2–3 times more relevant in women than men. This evidence suggests the effect of sex steroids such as 17β-estradiol (E2) on the reproductive tract [1]. There is a significant lack of translational research that explores basic mechanisms of functional syndromes. Visceral pain is different from cutaneous pain based on clinical, neurophysiological and pharmacological characteristics. Visceral pain is a complex phenomenon that occurs during activation of nociceptors from internal organs and shows great variability between patients [2, 3].

Spinal dorsal DRGs are an attractive therapeutic target for alleviating pain as they serve as a gate for the transmission of information prior to the central nervous system (CNS). Pain signaling is regulated within DRG before reaching the central nervous system, making these primary afferents an important target for therapy. Spinal interneurons integrate nociceptive sensory inputs from dorsal root ganglia to the dorsal horn and gate their access to spinal projection neurons, as was described by Ronald Melzack more than 50 years ago in the Gate Control Theory of Pain Processing [4]. Today, it is evidenced that dorsal horn interneurons limit access of non-nociceptive sensory input to nociceptive-specific projections in the spinal cord [5]. Chronic pain leads to hypersensitivity through convergence of nociceptive and non-nociceptive inputs on spinal projection neurons that signal to the primary somatosensory cortex.

Visceral sensitization is an important underlying contributor to chronic pain states but remains poorly understood. The mechanisms underlying how conduction is gated by depolarization or hyperpolarization of nociceptors and overall pain information through the DRG is of great interest to scientific and medical community. In this mini-review new insights on the cellular bases of visceral pain signaling in the peripheral and central nervous system are presented with potential to understand the complex neuronal regulation and reorganization of the nociceptive network.

Role of DRG in controlling pain signaling

Pain conduction through the DRG is influenced by hyperpolarization or depolarization of the plasma membrane. However, many available pain models do not account for heterogeneity of nociceptors as well as variations in neuronal fiber’s conductance. DRGs are not protected by the blood-brain barrier making these afferents an attractive pharmacological target for pain intervention. Significant CNS-associated side effects could be avoided. Manipulation of nociceptive sensory neurons may be an ideal therapy for visceral chronic pain.

DRGs have emerged as a promising neuromodulatory target to manage certain types of chronic pain, but it remains unknown whether and in what mechanisms visceral pain could be effectively attenuated by primary sensory neurons’ stimulation. Characterization of cellular mechanisms underlying the influence of DRG on nociception is an important step in the new line of research. DRG may act not just as a gate but also as a filter for pain transduction.

Differences in channel expression, between C, Aδ, and Ab fibers significantly affect the DRG properties and modulation of their conduction. Population of neurons affected by voltage- and ligand-channel activation may be sufficient to influence behavioral response to nociceptive stimuli. Depolarization can trigger depolarization block and inhibition of pain signaling in substantial number of neurons within the same ganglion. Indeed, many channelopathies are associated with neuropathic pain [6].

Visceral nociceptive (capsaicin-sensitive) C-fibers are activated by ATP and excitatory amino acids that are released by noxious stimuli from cells in target organs (paracrine action) or from afferent terminals themselves (autocrine action). DRG neurons innervating viscera have a greater [Ca²⁺]_i response to subsequent ATP, capsaicin and NMDA stimulation than somatic afferents [7]. These observations indicate that viscerally specific neurons express receptors with higher permeability to Ca²⁺, which can modulate transduction of nociceptive signals and suggest that visceral afferents are functionally different from somatic afferents. Sensitization of primary afferent neurons may play a role in the enhanced perception of visceral sensation leading to pain. Acute and recurrent/chronic pelvic pain in women or abdominal pain are all visceral pain sensations that may result from sensitization of sensory neurons [8]. Mechanisms of peripheral sensitization may involve an increase in the excitability of the afferent nerves by molecules that decrease the excitation threshold leading to sensitization.

Phosphorylation-dependent modulation of the vanilloid receptor TRPV1 is one of the key mechanisms mediating the hyperalgesic effects of inflammatory mediators, such as prostaglandin E2 (PGE2). Significantly, inflammation dramatically alters vanilloid-induced TRPV 1 receptor-mediated transduction and ATP-induced purinoception by causing a several fold increase in whole inward currents and enhances the expression of P2X receptors increasing neuronal hypersensitivity [8].

For over 50+ years “Gate Control Theory of Pain” by Ron Melzack explained why non-painful sensory input limits pain information from activating the CNS [4] but it is important to understand a novel form of pain filtering within DRG. Today, there is a strong body of evidence to support an integrative role of DRG primary afferent neurons in this process.

Visceral pain associated with functional diseases

Visceral pain is a complex phenomenon that occurs during activation of nociceptors from internal organs and shows great variability between patients. The incidence of episodic or persistent visceral pain is a significant burden for patients suffering from functional disorders but there is a significant lack of translational research that explores basic mechanisms of nociception. There are also variations of pain perception in a large percentage of female patients diagnosed with functional disorders. One of the hypotheses is that estrogen modulation of cross-sensitization of visceral inputs in the DRG accounts for the changes in pain perception in women with functional pain syndromes [1]. In order to further explore estrogen modulation of pain processing in periphery, medical research needs to reinforce a new strategy by focusing on possible cross-organ (i.e., utero-colon) visceral hyperalgesia in primary sensory afferents. A number of molecules and neurotropic factors are involved in hyperalgesia and overall sensory neuron sensitization. The inflammatory process produces mediators that activate nociceptors by interacting with ligand-gated ion channels or by sensitizing primary afferents. One mechanism for sensitization involves phosphorylation of ion channels and receptors including P2X3 and TRPV1 receptors. Inflammation does not change the percentage of total cells responding to ATP, but sensitizes the ATP response by increasing the expression of P2X3 [2]. Thus, the greater behavioral sensitivity during the inflammation is due to a two- to three-fold increase in ATP responses, suggesting that a small amount of ATP would evoke depolarization sufficient to elicit action potentials in DRG neurons. This pathological response arises from sensitization of DRG to external stimuli. Furthermore, inflamed tissues augment nociceptor responsiveness by acting on TRPV1. Gastrointestinal inflammation modulates the intrinsic properties of nociceptive DRG neurons, which innervate the gastrointestinal or urogenital tract. These changes are important in the genesis of abdominal pain and visceral hyperalgesia. Neurons exhibit hyperexcitability characterized by a decreased threshold for activation and increased firing rate. Inflammation up-regulates the activity of N-methyl-D-aspartate (NMDA) receptors, an inotropic glutamate receptor, in all DRG neurons within ganglia innervating viscera [9]. Sensitization may also account for a lowered nociceptive threshold to mechanical manipulation of the inflamed area.

Within the context of the cross-sensitization hypothesis, inflammation sensitizes non-inflamed viscera that are innervated by the same DRG, and/or cross-sensitization occurs as a result of intra-DRG release of sensitizing mediators such as ATP within the DRG [1, 2]. According to this new hypothesis, the reproductive tract inflammation sensitizes DRG neurons innervating the visceral organ. Several lines of evidence indicate that E2 directly influences the functions of primary afferent neurons. Both subtypes of estrogen receptors (ERα and ERβ) are present in DRG neurons, including the small-diameter putative nociceptors In vitro, ATP-sensitive and vanilloid-sensitive DRG neurons respond to E2, which supports the hypothesis that visceral afferents are E2 sensitive: i) visceral pain is affected by hormonal level in cycling females; ii) there are sex differences in the prevalence of functional disorders involving the viscera and iii) putative visceral afferents fit into the population of DRG neurons that are sensitive to E2. These data suggest that in addition to CNS actions, E2 can act in the periphery to modulate nociception.

Sex is a biological variable that is frequently ignored in study designs and analyses, leading to an incomplete understanding of potential sex-based differences in basic biological functions and disease processes. E2 has a significant role in modulating visceral sensitivity, indicating that E2 alterations in sensory processing may underlie sex-based differences in functional pain symptoms [10]. However, reports of E2 modulation of visceral and somatic nociceptive sensitivity are inconsistent. Indeed, in most clinical studies, women report more severe pain levels, more frequent pain and longer duration of pain than men. Studies of E2 actions on the primary afferents may help to resolve these inconsistencies and to suggest that DRG neurons are a potential target for pain treatment.

Significance and discussion

Chronic pain management is a major scientific and public health care challenge, as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. Sensitivity to pain remains long after tissue healing. The discovery of the neurochemical mechanisms that maintain chronic pain hypersensitivity is needed for a better treatment. The outcome of the studies focused on new mechanisms of visceral pain will have a substantial impact on our knowledge of pain-associated diseases and may help to achieve a deeper understanding of gender differences presented in clinical aspects of the functional syndromes such as irritable bowel syndrome, chronic pelvic pain, interstitial cystitis/painful bladder syndrome, fibromyalgia and others.

Chronic visceral pain is one of the leading causes of global disability, impacting quality-of-life of millions of individuals worldwide. Despite the huge unmet medical need, existing treatments are often ineffective or are associated with unwanted consequences. Chronic pain is maintained, in part, by persistent changes in primary afferent sensory neurons (Figure 1). According to our model, neuromodulation targets afferent sensory signaling in chronic pain syndromes. Spinal cord stimulation targets afferent projections to the dorsal spinal cord relieving visceral pain arising from the visceral organs. Neuroregulation of the nociceptive system is likely evolved as defense mechanisms that allowed for protection of the body during nocieption. However, in chronic pain this protective mechanism does not resolve. It is also well-established that the development of chronic visceral pain results in part from sustained glial cells remodeling resulting in the release of pro-inflammatory molecules that activate pain circuits centrally and peripherally. Pain pathways are activated in virtually all human diseases and only a thorough understanding of the mechanism implicated in the functional painful disorders can truly contribute to more efficient therapies significantly reducing therapeutic interventions, and new approach is needed to identify potentially new therapeutic targets to address visceral pain modalities.

Figure 1.

Conceptual model of altered sensation and sensory neurons’ remodeling in clinical aspects of functional diseases associated with visceral pain.

CONCLUSION

Chronic visceral pain represents a significant health problem worldwide with women being disproportionately affected, and constitutes a serious threat associated with overuse of anti-pain medications. Treatment options for chronic pain are often limited and significant side effects include risk of addiction. Therefore, new pain therapies based on detailed understanding of chronic pain mechanisms are needed as alternatives to current analgesics.