Synthesis and release of inflammatory mediators and activation of macrophages

Synthesis and release of inflammatory mediators and activation of macrophages, mast cells and dendritic following inflammatory response lead to acute or chronic signs of inflammation. The acute phase of inflammation is characterized by the rapid influx of blood granulocytes, typically neutrophils, followed swiftly by monocytes that mature into inflammatory macrophages that subsequently proliferate and thereby affect the functions of resident tissue macrophages. This process causes the cardinal signs of acute inflammation: redness), heat, swelling) and pain (Ricciotti and FitzGerald, 2011). In the vascular system, acute inflammatory response causes vasodilation and consequent increased vascular flow; increased vascular permeability and leucocytes migration. Histamine and 5-hydroxy tryptamine are usually responsible for eliciting the immediate response of inflammation whereas kinins and prostaglandins mediate the more prolonged delayed onset responses (Shikha et al., 2010).
Through the action of regulatory cytokines such as IL-10, the initiating noxious stimulus is removed via phagocytosis after which the inflammatory reaction is decreased and resolved (Rojas-López et al., 2012; Joshi et al., 2016). Rather than persistence dysfunction which can lead to scarring and loss of organ function, the usual outcome of the acute inflammatory program is successful resolution and repair of tissue damage. It may be anticipated, therefore, that failure of acute inflammation to resolve may predispose to chronic inflammatory disorders such as, rheumatoid arthritis, osteoarthritis, psoriasis, and inflammatory bowel disease (Feldmann et al., 1996; Neogi, 2016).
These inflammatory disorders are identified as a major cause of morbidity worldwide (Dewanjee et al., 2013). Inflammation is usually managed with non-steroidal anti-inflammatory drugs (NSAIDs). However these agents are usually associated with serious adverse effects and their affordability is a concern (Croff, 2013). In chronic pain conditions, for example, the utilization of NSAIDs accompanies severe toxicities including gastric and renal adverse effects (Sostres et al., 2010). Thus the current health care system needs inclusion of newer anti-inflammatory drugs with minimal adverse effect, improved efficacy and at affordable cost
Worldwide, many natural products are used as part of the traditional medical system to control symptoms of inflammatory disorders. Therefore, investigation of natural remedies is required to efficiently control the pain and inflammation with least side effects (Riedel et al., 2015). One way of drug discovery is screening natural products through different animal models (Hossain et al., 2010). Among the different inflammation models, carrageenan induced paw edema model is well-known to investigate the anti-inflammatory activities of various synthetic or natural compounds (Di Rosa et al., 1971; (Halici et al., 2007).
1.2 Pain
International association for the study of pain (IASP) defines pain as unpleasant sensory and emotional experience associated with actual or potential tissue damage, or describe in terms of such damage (IASP, 1979). Pain serves as a warning of impending injury, triggering appropriate protective response that threatens the integrity of cells or tissues (Bonica, 1979). Chronic pain, however, is a pathological condition that does not serve any useful purpose, but results in a rather substantial loss of quality of life. Indeed, chronic pain is one of the most common and costly health problems (Dubuison, 2006).
On the basis of pathophysiology, pain can be classified as nociceptive and neuropathic. Nociceptive pain is caused by the ongoing activation of A? and C-nociceptors in response to a noxious stimulus and serves a function of indicating real or potential tissue damage (Demerol, 2000).
Activation of the free nerve endings with chemical, physical or noxious thermal stimuli results in release of inflammatory mediators like histamine, calcitonin gene-related peptide (CGRP), BK, serotonin (5-HT), LTs, PGs and, substance P from injured tissues (Fig.2). Then inflammatory mediators will lead to activation or sensitization of nociceptors (Basbun, 2001).
Once sensitization of nociceptors occurs, the action potential generated is propagated through the primary afferent nerve fibers to the spinal cord where they synapse with second order neurons in the grey matter of the dorsal horn. Thereafter, second order neurons from spinal cord project their axons to brain stem or to the thalamocortical system that produces the conscious pain in response to noxious stimuli (Fields and Basbaum, 1978).
Neuropathic pain is caused by aberrant signal processing in the peripheral or central nervous system. After peripheral nerve injury, damaged and non-damaged A and C-fibers begin to generate spontaneous action potentials. Lesions alter the structure and function of the somatosensory nervous system so that pain occurs spontaneously and responses to noxious and innocuous stimuli are pathologically amplified (Latremoliere and Woolf, 2009). Any process that causes damage to the nerves, such as metabolic, traumatic, infectious, ischemic, toxic or immune-mediated pathological conditions, can result in neuropathic pain. In addition, neuropathic pain can be caused by nerve compression or the abnormal processing of pain signals by the brain and spinal cord. Neuropathic pain can be either peripheral (arising as a direct consequence of a lesion or disease affecting the peripheral nerve, the dorsal root ganglion or dorsal root) or central (arising as a direct consequence of a lesion or disease affecting the CNS). However, a clear distinction is not always possible (Ewan and Smith, 2017)