Preclinical Assessment of Inflammatory Pain

Abstract

While acute inflammation is a natural physiological response to tissue injury or infection, chronic inflammation is maladaptive and engenders a considerable amount of adverse pain. The chemical mediators responsible for tissue inflammation act on nociceptive nerve endings to lower neuronal excitation threshold and sensitize afferent firing rate leading to the development of allodynia and hyperalgesia, respectively. Animal models have aided in our understanding of the pathophysiological mechanisms responsible for the generation of chronic inflammatory pain and allowed us to identify and validate numerous analgesic drug candidates. Here we review some of the commonly used models of skin, joint, and gut inflammatory pain along with their relative benefits and limitations. In addition, we describe and discuss several behavioral and electrophysiological approaches used to assess the inflammatory pain in these preclinical models. Despite significant advances having been made in this area, a gap still exists between fundamental research and the implementation of these findings into a clinical setting. As such we need to characterize inherent pathophysiological pathways and develop new endpoints in these animal models to improve their predictive value of human inflammatory diseases in order to design safer and more effective analgesics.

Keywords: Animal models; Arthritis; Behavior; Cutaneous pain; Inflammation; Laboratory assessment; Nociception; Visceral pain.

Figure 1

A schematic illustrating peripheral sensitization of a free nerve ending by various inflammatory mediators and irritant substances. Capsaicin, mustard oil, acid, and formalin increase the sensitivity of neurones by opening transient receptor potential vanilloid type 1 (TRPV1) ion channels, which leads to the release of neuropeptides such as substance P (SP) and vasoactive intestinal peptide (VIP). Locally released SP binds to neurokinin 1 (NK1) receptors and VIP binds to VPAC1 receptors. Histamine released from mast cells acts on neuronal H1 receptors. Leukocytes and mast cell release serine proteases which subsequently cleave various proteinase‐activated receptors (PAR) leading to downstream nociceptor modulation. Toll‐like receptor 4 (TLR4) is activated by exogenous substances like carrageenan and lipopolysaccharides (LPS), while leukocyte‐derived cytokines like tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), and interleukin‐17 (IL‐17) bind to their respective receptors to enhance pain transmission. Prostaglandin E2 (PGE ₂) mainly activates the PGE ₂ receptor and sensitizes sensory neurones to environmental stimuli.