Mechanisms and Management of Chronic Pain.

Chronic pain symptoms account up to half of all health care visits, afflicts >10% of US adults, at a higher prevalence in women with current analgesic drugs rarely provide enough efficacy in the absence of serious side effects. Chronic pain is also the root cause of the national opioid health crisis, which adds to health care costs and deaths. Thus, new pain therapies based on detailed understanding of nociceptive mechanisms are needed as alternatives to opioid analgesics and are of great societal importance.

Peripheral modulation of chronic visceral pain.

Chronic visceral pain is a complex and often a serious burden on patients' life. It is strongly implicated in the etiology of many diseases, which often are complicated by co-morbid depression and other psychiatric disorders, all of which pose significant health risks. Understanding the mechanisms of nociception is an important step in treating pain-associated chronic diseases.

Neural reorganization associated with visceral pain.

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.

Visceral nociception and functional diseases.

This mini-review summarizes the different pain-associated diseases and potential mechanisms that may help to achieve a deeper understanding of gender differences presented in clinical aspects of the functional syndromes. Chronic visceral pain is the most common complication of many functional disorders that do not have a defined pathophysiological cause. Functional pain syndromes include common disorders such as Irritable Bowel Syndrome (Gastroenterology), Interstitial Cystitis/Painful Bladder Syndrome (Urology), Fibromyalgia (Rheumatology), and Chronic Pelvic Pain (Gynecology) and cross multiple medical disciplines.

Visceral pain modulation in female primary afferent sensory neurons.

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.

Physically disconnected non-diffusible cell-to-cell communication between neuroblastoma SH-SY5Y and DRG primary sensory neurons.

Background: Cell-cell communication occurs via a variety of mechanisms, including long distances (hormonal), short distances (paracrine and synaptic) or direct coupling via gap junctions, antigen presentation, or ligand-receptor interactions. We evaluated the possibility of neuro-hormonal independent, non-diffusible, physically disconnected pathways for cell-cell communication using dorsal root ganglion (DRG) neurons.

Methods: We assessed intracellular calcium ([Ca(2+)]) in primary culture DRG neurons that express ATP-sensitive P2X3, capsaicinsensitive TRPV1 receptors modulated by estradiol.

Estrogen modulation of visceral nociceptors.

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 dorsal root ganglion (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 P2X and vanilloid TRPV1 receptors and 17β-estradiol modulates DRG neuron response to ATP (P2X agonist) and capsaicin (TRPV1 agonist) suggesting that visceral afferent nociceptors are modulated by estrogen in the DRG.

Expression of P2X3 and TRPV1 receptors in primary sensory neurons from estrogen receptors-α and estrogen receptor-β knockout mice.

In women, pain symptoms and nociceptive thresholds vary with the reproductive cycle, suggesting the role of estrogen receptors (ERs) in modulating nociception. Our previous data strongly suggest an interaction between ERs and ATP-induced purinergic (P2X3) as well as ERs and capsaicin-induced vanilloid (TRPV1) receptors at the level of dorsal root ganglion (DRG) neurons. In this study, we investigated the expression of P2X3 and TRPV1 receptors by western blotting and immunohistochemistry in lumbosacral DRGs from wild type, ERα, and ERβ knockout mice.

Estrogen and Visceral Nociception at the Level of Primary Sensory Neurons.

Clinical studies suggest the comorbidity of functional pain syndromes such as irritable bowel syndrome, painful bladder syndrome, chronic pelvic pain, and somatoform disorders approaches 40% to 60%. The incidence of episodic or persistent visceral pain associated with these "functional" disorders is two to three times higher in women than in men. One of the possible explanations for this phenomenon is estrogen modulation of viscerovisceral cross-sensitization.

Estradiol attenuates the adenosine triphosphate-induced increase of intracellular calcium through group II metabotropic glutamate receptors in rat dorsal root ganglion neurons.

Estradiol attenuates the ATP-induced increase of intracellular calcium concentration ([Ca(2+)](i)) in rat dorsal root ganglion (DRG) neurons by blocking the L-type voltage gated calcium channel (VGCC). Because ATP is a putative nociceptive signal, this action may indicate a site of estradiol regulation of pain. In other neurons, 17β-estradiol (E(2)) has been shown to modulate L-type VGCC through a membrane estrogen receptor-group II metabotropic glutamate receptor (mGluR(2/3)).

Peripheral sensitization of sensory neurons.

Introduction: Defining the sites and mechanisms of nociception is an important step in understanding and treating pain. During inflammation, increased nociceptive input from an inflamed organ can sensitize neurons that receive convergent input from an unaffected organ, but the site of visceral cross-sensitivity is unknown. This study examined the cellular responses to ATP and substance P stimulation in sensory neurons innervating visceral organs.

Visceral sensory neurons that innervate both uterus and colon express nociceptive TRPv1 and P2X3 receptors in rats.

In women, clinical studies suggest that functional pain syndromes such as irritable bowel syndrome, interstitial cystitis, and fibromyalgia, are co-morbid with endometriosis, chronic pelvic pain, and others diseases. One of the possible explanations for this phenomenon is visceral cross-sensitization in which increased nociceptive input from inflamed reproductive system organs sensitize neurons that receive convergent input from an unaffected visceral organ to the same dorsal root ganglion (DRG). The purpose of this study was to determine whether primary sensory neurons that innervate both visceral organs--the uterus and the colon--express nociceptive ATP-sensitive purinergic (P2X3) and capsaicin-sensitive vanilloid (TRPV1) receptors.

Inflammation in the uterus induces phosphorylated extracellular signal-regulated kinase and substance P immunoreactivity in dorsal root ganglia neurons innervating both uterus and colon in rats.

In women, clinical studies suggest that pain syndromes such as irritable bowel syndrome and interstitial cystitis, which are associated with visceral hyperalgesia, are often comorbid with endometriosis and chronic pelvic pain. One of the possible explanations for this phenomenon is viscerovisceral cross-sensitization, in which increased nociceptive input from an inflamed pelvic organ sensitizes neurons that receive convergent input to the same dorsal root ganglion (DRG) from an unaffected visceral organ. Nociception induces up-regulation of cellular mechanisms such as phosphorylated extracellular signal-regulated kinase (pERK) and substance P (SP), neurotransmitters associated with induced pain sensation.

The same dorsal root ganglion neurons innervate uterus and colon in the rat.

The purpose of this study was to determine whether primary sensory neurons that innervate the uterus receive convergent input from the colon. To test this, in the rat, cell bodies of colonic and uterine dorsal root ganglia were retrogradely labeled with fluorescent tracer dyes microinjected into the colon/rectum and bilaterally into the uterine horns. Ganglia were harvested, cryoprotected and cut into 20 microm slices to identify positively stained cells for fluorescent microscopy.

Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures.

The brain synthesizes steroids de novo, especially progesterone. Recently estradiol has been shown to stimulate progesterone synthesis in the hypothalamus and enriched astrocyte cultures derived from neonatal cortex. Estradiol-induced hypothalamic progesterone has been implicated in the control of the LH surge.

Estrogen receptor-alpha mediates estradiol attenuation of ATP-induced Ca2+ signaling in mouse dorsal root ganglion neurons.

A mechanism underlying gender-related differences in pain perception may be estrogen modulation of nociceptive signaling in the peripheral nervous system. In rat, dorsal root ganglion (DRG) neurons express estrogen receptors (ERs) and estrogen rapidly attenuates ATP-induced Ca2+ signaling. To determine which estrogen receptor mediates rapid actions of estrogen, we showed ERalpha and ERbeta expression in DRG neurons from wild-type (WT) female mice by RT-PCR.

A membrane estrogen receptor mediates intracellular calcium release in astrocytes.

Appreciating the physiology of astrocytes and their role in brain functions requires an understanding of molecules that activate these cells. Estradiol may influence astrocyte functions. We now report that estrogen altered intracellular calcium concentration ([Ca(2+)](i)) in neonatal astrocytes that expressed estrogen receptor (ER) mRNA in vitro.

Oestrogen modulates cholecystokinin: opioid interactions in the nervous system.

Responses of the nervous system to introceptive and extroceptive inputs depend upon the state of the brain. Oestrogen has the ability to modulate brain state and dramatically alter interactions among neural circuits to influence an organism's responses to given stimuli. Cholecystokinin (CCK) and endogenous opioid peptides (EOP) have a wide and parallel distribution in the nervous system.