Casey O. Ligon

Targeting Epigenetic Mechanisms for Chronic Pain: A Valid Approach for the Development of Novel Therapeutics.

Chronic pain is a multifaceted and complex condition. Broadly classified into somatic, visceral, or neuropathic pain, it is poorly managed despite its prevalence. Current drugs used for the treatment of chronic pain are limited by tolerance with long-term use, abuse potential, and multiple adverse side effects. The persistent nature of pain suggests that epigenetic machinery may be a critical factor driving chronic pain. In this review, we discuss the latest insights into epigenetic processes, including DNA methylation, histone modifications, and microRNAs, and we describe their involvement in the pathophysiology of chronic pain and whether epigenetic modifications could be applied as future therapeutic targets for chronic pain. We provide evidence from experimental models and translational research in human tissue that have enhanced our understanding of epigenetic processes mediating nociception, and we then speculate on the potential future use of more specific and selective agents that target epigenetic mechanisms to attenuate pain.

Epigenetics of Pain Management

Abstract Although currently available therapeutics provide moderate relief from acute pain, therapeutic agents used for treating chronic pain are typically limited by adverse side effects, including tolerance, addiction, and constipation. Thus, there is a significant medical need for novel therapies devoid of serious adverse effects for the treatment of chronic pain. Histone deacetylase inhibitors and other epigenetic drugs, such as histone acetlytransferases inhibitors, have been shown to have a role in managing pain perception. This chapter will briefly review spinal and central pain pathways mediating nociception. We will discuss the animal models, which have enhanced our understanding of how epigenetic processes may play a role in the pathophysiological mechanisms of chronic pain. We will also review the basic molecular epigenetic mechanisms of pain processing, and throughout the chapter the authors have attempted to critically evaluate the latest research from both experimental animal models and human studies to highlight the role of epigenetic drugs in managing both acute and chronic pain. However, it is pertinent to note that the role of epigenetics in pain perception is a field in its infancy, and thus limited data is to hand of the exact molecular mechanisms that mediate pain perception.

Enteric RET inhibition attenuates gastrointestinal secretion and motility via cholinergic signaling in rat colonic mucosal preparations

The expression of RET in the developing enteric nervous system (ENS) suggests that RET may contribute to adult intestinal function. ENS cholinergic nerves play a critical role in the control of colonic function through the release of acetylcholine (ACh). In the current study, we hypothesized that a RET‐mediated mechanism may regulate colonic ion transport and motility through modulation of cholinergic nerves.

Linaclotide inhibits colonic and urinary bladder hypersensitivity in adult female rats following unpredictable neonatal stress

Irritable bowel syndrome (IBS) and bladder pain syndrome (BPS) are female‐predominant, chronic functional pain disorders that are associated with early life stress (ELS) and therapeutic options for such patients remain limited. Linaclotide, a guanylate cyclase‐C (GC‐C) agonist, relieves abdominal pain and bowel symptoms in adult patients suffering from IBS with constipation. Here, we test the hypothesis that linaclotide will reverse colon and bladder hyperalgesia in a female‐specific rodent model of adverse early life experience.

Linaclotide Attenuates Visceral Organ Crosstalk: Role of Guanylate Cyclase-C Activation in Reversing Bladder-Colon Cross-Sensitization

Bladder pain syndrome (BPS) is poorly understood; however, there is a female predominance and comorbidity with irritable bowel syndrome (IBS). Here we test the hypothesis that linaclotide, a guanylate cyclase-C (GC-C) agonist approved for the treatment of IBS with constipation (IBS-C), may represent a novel therapeutic for BPS acting through a mechanism involving an inhibition of visceral organ cross-sensitization. We showed previously that infusion of dilute protamine sulfate (PS) into the bladder increased sensitivity and permeability in the bladder and colon. PS was infused into the bladder of female rats; sensitivity was assessed via application of von Frey filaments applied to the suprapubic area and the frequency of withdrawal responses was recorded. Colonic sensitivity was measured via visceromotor behavioral response to graded pressures of colorectal distension (CRD). Permeability was measured in vitro via transepithelial electrical resistance (TEER) and conductance (G). Linaclotide (3 µg/kg, p.o.) or vehicle was administered daily for 7 days prior to experiments. Rats treated with PS bladder infusion exhibited visceral hyperalgesia, as shown by a significantly higher response frequency to individual von Frey filaments and increased behavioral responses to CRD. Linaclotide attenuated bladder and colonic hyperalgesia to control levels. PS infusion into the bladder increased bladder and colon permeability measured as a decrease in TEER and increased G. Linaclotide significantly inhibited PS-induced colonic hyperpermeability while having no effect on bladder hyperpermeability. Our findings suggest a novel treatment paradigm for GC-C agonism in IBS-C and BPS mediated through a mechanism involving visceral organ crosstalk.

Visceral hypersensitivity induced by optogenetic activation of the amygdala in conscious rats

In vivo optogenetics identifies brain circuits controlling behaviors in conscious animals by using light to alter neuronal function and offers a novel tool to study the brain-gut axis. Using adenoviral-mediated expression, we aimed to investigate whether photoactivation with channelrhodopsin (ChR2) or photoinhibition with halorhodopsin (HR3.0) of fibers originating from the central nucleus of the amygdala (CeA) at the bed nucleus of the stria terminalis (BNST) had any effect on colonic sensitivity. We also investigated whether there was any deleterious effect of the adenovirus on the neuronal population or the neuronal phenotype within the CeA-BNST circuitry activated during the optogenetic stimulation. In male rats, the CeA was infected with vectors expressing ChR2 or HR3.0 and fiber optic cannulae were implanted on the BNST. After 8-10 wk, the response to graded, isobaric colonic distension was measured with and without laser stimulation of CeA fibers at the BNST. Immunohistochemistry and histology were used to evaluate vector expression, neuronal integrity, and neurochemical phenotype. Photoactivation of CeA fibers at the BNST with ChR2 induced colonic hypersensitivity, whereas photoinhibition of CeA fibers at the BNST with HR3.0 had no effect on colonic sensitivity. Control groups treated with virus expressing reporter proteins showed no abnormalities in neuronal morphology, neuronal number, or neurochemical phenotype following laser stimulation. Our experimental findings reveal that optogenetic activation of discrete brain nuclei can be used to advance our understanding of complex visceral nociceptive circuitry in a freely moving rat model. NEW & NOTEWORTHY Our findings reveal that optogenetic technology can be employed as a tool to advance understanding of the brain-gut axis. Using adenoviral-mediated expression of opsins, which were activated by laser light and targeted by fiber optic cannulae, we examined central nociceptive circuits mediating visceral pain in a freely moving rat. Photoactivation of amygdala fibers in the stria terminalis with channelrhodopsin induced colonic hypersensitivity, whereas inhibition of the same fibers with halorhodopsin did not alter colonic sensitivity.

PD01-12 BLADDER HYPERPERMEABILITY INDUCES PERSISTENT VISCERAL PAIN: A NOVEL MECHANISM FOR VISCERAL ORGAN CROSSTALK

(17.1 vs 14.3, 4.3 vs 3.6, p <0.001 for both). The complication rate during the study period was 0.83% and comprised an extraperitoneal bladder perforation managed conservatively, anaphylaxis to DMSO instillation, and transient tachycardia with hypotension. CONCLUSIONS: Repeated hydrodistention did not decrease bladder capacity over time and development of ulceration was rare. In this cohort of patients it had significant positive effects on symptom control and quality of life. Hydrodistention is a safe procedure with low complication rates.