Pharmacology of Inflammatory Pain: Local Alteration in Receptors and Mediators

Abstract

Background: Inflammation is commonly associated with hyperalgesia. Ideally, this change should abate once inflammation is resolved, but this is not necessarily the case because phenotypic changes in the tissue can persist, as appears to be the case in post-infectious irritable bowel syndrome. Basically, all primary afferent neurons supplying the gut can be sensitized in response to pro-inflammatory mediators, and the mechanisms whereby hypersensitivity is initiated and maintained are, thus, of prime therapeutic interest. Experimental and Clinical Findings: There is a multitude of molecular nocisensors that can be responsible for the hypersensitivity of afferent neurons. These entities include: (i) receptors and sensors at the peripheral terminals of afferent neurons that are relevant to stimulus transduction, (ii) ion channels that govern the excitability and conduction properties of afferent neurons, and (iii) transmitters and transmitter receptors that mediate communication between primary afferents and second-order neurons in the spinal cord and brainstem. Persistent increases in the sensory gain may result from changes in the expression of transmitters, receptors or ion channels; changes in the subunit composition and biophysical properties of receptors and ion channels; or changes in the structure, connectivity and survival of afferent neurons. Particular therapeutic potential is attributed to targets that are selectively expressed by afferent neurons and whose number and function are altered in abdominal hypersensitivity. Conclusion: Emerging targets of therapeutic relevance include distinct members of the transient receptor potential (TRP) channel family (TRPV1, TRPV4, TRPA1), acid-sensing ion channels, protease-activated receptors, corticotropin-releasing factor receptors and sensory neuron-specific sodium channels.

Selective potentiation of 2-APB-induced activation of TRPV1–3 channels by acid

“…Tissue acidosis is an important contributing factor to pain and inflammation 34 . Ion channels are critically involved in acid sensing under physiological and pathophysiological conditions 34 .…”

“…Tissue acidosis is an important contributing factor to pain and inflammation 34 . Ion channels are critically involved in acid sensing under physiological and pathophysiological conditions 34 . The initial functional characterizations of both human and murine TRPV3 had indicated that the channel was not activated by low pH 17 20 21 .…”

Effect of DA-9701 on Colorectal Distension-Induced Visceral Hypersensitivity in a Rat Model

“…Similarly, intolerance to gastric distension was documented in patients with functional dyspepsia 6,7. Some attempts have already been made to pharmacologically decrease the visceral hypersensitivity of functional GI disorders, using a number of drugs 8,9. However, the treatment was not satisfactory and the side effects could not be easily overcome.…”

Effect of Red Pepper on Symptoms of Irritable Bowel Syndrome: Preliminary Study

“…Some attempts have already been made to decrease pharmacologically the visceral sensitivity of functional gut disorders with a number of drugs [17], such as fedotozine, octreotide, clonidine, anti-inflammatory compounds, tricyclic antidepressants and antagonists of 5HT 3 , CRF, CCK and bradykinin, etc. However, most of these substances, although able to increase, at least experimentally, the colonic sensory threshold, are at the moment not commercially available, because being still under investigation or, if commercially available, do not represent a reliable chronic treatment for IBS pain, because of marginal clinical benefits, absence of a predominant selective effect on visceral hypersensitivity, lack of controlled studies and possible dangerous side effects during chronic treatments.…”