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A Surgical Opinion on Hyperalgesia/Nociception

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A Surgical Opinion on Hyperalgesia/Nociception Send Orders of Reprints at [email protected] Current Immunology Reviews, 2012, 8, 275-286 275 A Surgical Opinion on Hyperalgesia/Nociception, Inflammatory/Neurogenic Pain and Anti-inflammatory Responses and Drug Interventions Revisited: Current Breakthroughs and Views John J. Haddad* Cellular and Molecular Physiology and Immunology Signaling Research Group, Biomedical Laboratory and Clinical Sciences Division, Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon Abstract: All sensory modalities are essentially important, but pain serves a protective function and is indispensable for survival, and, technically, pain is considered one of the most common symptoms of injuries and related diseases. Inflammatory cells and inflammatory mediators are crucially involved in the propensity, genesis, persistence and severity of pain, commonly known as nociception or hyperalgesia, following trauma, infection, or nerve injury. When it pins down to the essential understanding of pain/hyperalgesia pathways and their intricate interactions with myriad probabilities of milieu of inflammatory cytokines and related molecules, the amicable concept of specificity and complexity remains a major dilemma. Various hyperalgesic models have been established to investigate this intricate relationship between pain perception and inflammatory responses. Illness-induced hyperalgesia, for instance, is one of the most common aspects of pain related-inflammation and therapeutic approach to this pain should aim at interfering with various mediators of the inflammatory reactions, including neuropeptides, eicosanoids and cytokines. In this surgical synopsis, a trajectory of neurochemical events and cascades are delineated and unraveled in terms of the connection that has ostensibly evolved for hyperalgesia-inflammatory responses. The unprecedented intricacy of pain-inflammatory relationship and putative pathways bears surmountable clinical and physiological relevance. Keywords: Cytokines, endotoxin, hyperalgesia, inflammation, neurochemistry, neurogenic, nociception, pain. 1. INTRODUCTION AND SURGICAL BACKGROUND increases in intensity over a period of several seconds or minutes. Impulses for slow pain conduct along small- All of our sensory modalities are essentially important, diameter, unmyelinated C fibers. This type of pain may be but pain serves a protective function and is indispensable for excruciating and often has a burning, aching, or throbbing survival. Pain is technically the most common symptom of quality [1, 2]. Pain that arises from stimulation of receptors injuries and diseases [1]. The International Association for in the skin is called superficial somatic pain; stimulation of the Study of Pain (IASP) developed a consensus definition receptors in skeletal muscles, joints, tendons, and fascia of pain; according to the IASP, “pain is an unpleasant bodily causes deep somatic pain. Visceral pain results from sensory experience commonly produced by processes that stimulation of nociceptors in visceral organs. In many damage, or are capable of damaging [or inducing noxious instances of visceral pain, the pain is felt in or just deep to damage of], bodily tissue”. Nerve cell endings, or receptors, the skin that overlies the stimulated organ, or in a surface commonly known as nociceptors “(noci- is derived from the area far from the stimulated organ. This phenomenon is Latin for “hurt”)”, are central to pain sensation and called referred pain (Fig. 1) [1]. assessment. Nociceptors are chemoreceptive free nerve endings activated by tissue damage from intense thermal, A nociceptive stimulus at the nerve endings unleashes a mechanical, or chemical stimuli; they are found in virtually cascade of events throughout the nervous system, which can every tissue of the body except the brain. Nociceptors, ultimately lead (and loop) back to the site of injury. This thereby, have the ability to relay information to the central response prompts cells of a variety of types in the injured nervous system (CNS), particularly the brain, thus indicating area to release chemicals and neurochemicals that trigger an the location, nature and intensity of the ensuing pain [1]. immune response and thus influence the intensity and duration of pain [1, 2]. The inflammatory milieu that usually Technically, there are two types of pain: i) fast and ii) precedes, and accompanies, pain is, purportedly, slow. The perception of fast pain (acute, well localized) transcriptionally regulated, such as with the nuclear factor occurs rapidly because the nerve impulses propagate along (NF)-B, a major transcription factor, essentially involved in medium-diameter, myelinated A fibers. By contrast, slow mediating inflammatory processes and the release of pain begins after a stimulus is applied and gradually inflammatory mediators [1]. Current strategies aiming at controlling the origin, and propagation, of pain, as well as its manifestations, reveal the crucial role that this transcription *Address correspondence to this author at the Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, factor has in modulating pain and nociception, following the Beirut, Lebanon; Tel: +961 1 300 110; Fax: +961 1 378 159; ensuing inflammatory cascade. In lieu with the E-mail: [email protected] aforementioned description, the author quotes a technical 1875-631X/12 $58.00+.00 © 2012 Bentham Science Publishers 276 Current Immunology Reviews, 2012, Vol. 8, No. 4 John J. Haddad Fig. (1). Schematics of nociceptors and common pain patterns/modules. (A) The nerve free ending of a nociceptor. Nociceptors are chemoreceptive free nerve endings activated by tissue damage from intense thermal, mechanical, or chemical stimuli. (B) Common patterns of referred visceral pain are shown in this graphic: (a) anterior and (b) posterior views. (Adapted, courtesy of Tortora et al., Principles of Anatomy and Physiology, 13th edition, 2012, John Wiley & Sons Publishers). note identifying the natural and current themes pertaining to pain, commonly known as nociception or hyperalgesia, inflammatory hyperalgesia and nociception pathways [1, 2]. following trauma, infection or nerve injury [1, 2]. It is essentially conspicuous that when studying hyperalgesia and “A natural assumption is that the sensation of pain arises inflammatory responses that animal, and recently human, from excessive stimulation of the same receptors that generate other somatic sensations. This is not [usually] the case. models can play an important role in the development, screening and evaluation of analgesic and anti-inflammatory Although similar in some [and probably in many] ways to the actions of clinical drugs [1, 2]. The availability of appropriate sensory processing of ordinary mechanical stimulation, the models, therefore, is of particular importance, if not crucial, for perception of pain (called nociception) depends on specifically such investigations [3, 4]. Different models have been utilized; dedicated receptors and pathways. Since alerting the brain to as an illustration, carrageenan, a polysaccharide extracted from the dangers implied by noxious stimuli differs substantially from informing it about innocuous somatic sensory stimuli, it makes the cell wall of red algae, has been used to induce peripheral inflammation and edema, restricted to the injected paw [5, 6]. good sense that a special subsystem be devoted to the This model has been, for example, used to evaluate the effects perception of potentially threatening circumstances. The of non-steroidal anti-inflammatory drugs (NSAIDs) [6, 7]. overriding importance of pain in clinical practice, as well as the Other studies have used the complete Freund’s adjuvant (CFA), many aspects of pain physiology and pharmacology that remain which contains attenuated heat-killed Mycobacteria in the imperfectly understood, continue to make nociception an extremely active [and burgeoning] area of research”. (Adapted, water-in-oil emulsion, which induces a severe inflammation of the injected hind paw characterized by erythema, edema and Scott T. Brady et al., In: Basic Neurochemistry: Principles of th hyperalgesia with a peak response lasting for several days post Molecular, Cellular, and Medical Neurobiology, 8 edition, induction [1, 2]. 2012, Academic Press Publishers). Localized and central endotoxin (ET) administration, Inflammatory cells and inflammatory mediators are crucially involved in the genesis, persistence and severity of another projected inflammatory model, has been shown to Hyperalgesia and Inflammatory Responses Current Immunology Reviews, 2012, Vol. 8, No. 4 277 induce, when injected intraperitoneally, systemic and, if set free, induce in mammalians potent hyperalgesia mediated by cytokines, which are released from pathophysiological effects (see Fig. 2). Chemically, they are the Kupffer cells and acting through the vagal nerve [8-10]. LPSs consisting of an O-specific chain, a core In addition, various models were utilized to induce, for oligosaccharide and a lipid component, termed lipid A, example, arthritic inflammation. CFA produced slow whose partial structures proved that the expression of arthritis when injected into joints of animals, and cytokines endotoxic activity depends on a unique primary structure and can induce similar effect [11]. Sodium urate has been also a peculiar endotoxic conformation. When bacteria multiply, used for the evaluation of analgesic and anti-inflammatory
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