Chapter 6 - Nociceptors: thermal allodynia and thermal pain
Introduction
Pain is an unpleasant or distressing feeling, often associated with intense or damaging stimuli. The sensation of pain serves a vital protective function, alerting the individual of real or impending injury to the skin and internal tissues. Acute pain, evoked by intense stimuli, has an obvious adaptive role, triggering behaviors that limit exposure and minimize further tissue damage. In contrast, under certain pathologic conditions, pain can be become persistent. In this chronic pain state, very often, the generation of pain can be triggered by stimuli normally perceived as innocuous. This increased sensitivity to pain is called pain allodynia (Loeser and Treede, 2008). In this situation, pain becomes maladaptive and impacts negatively on the quality of life of the affected individual, and may result in persistent alterations in sensory perception and brain structure even after the initiating painful stimulus has resolved; pain has turned from a symptom into a chronic disease (May, 2008). Many pathologic pain conditions are poorly understood and, very often, their treatment is unsatisfactory, resulting in many patients failing to obtain adequate pain relief with the available therapies.
Detection of potentially damaging stimuli is performed by a specialized subset of cutaneous and visceral nerve endings known as nociceptors (Basbaum et al., 2009; Woolf, 2011). Once activated, these endings generate trains of action potentials that are forwarded to the central nervous system, relaying information on the onset, duration, location, intensity, and modality of the peripheral stimulus, finally giving rise to reflex actions or a conscious sensation.
The term nociceptor was coined by the British neurophysiologist Charles Sherrington over a century ago, to emphasize the noxious nature of their adequate stimulus (intense pressure, low or elevated temperatures, and irritating chemicals) in contrast with the low-threshold mechano- and thermal receptors that signal innocuous forces and serve to detect nonnoxious changes in the environment.
Electrophysiologic studies, including microneurography in conscious human subjects, have identified different nociceptor subtypes, based on their pattern of response to specific stimuli (Schmidt et al., 1995). They include polymodal nociceptors (excited by mechanic, thermal, and chemical stimuli), mechano-cold and heat nociceptors (Woolf and Ma, 2007). Some nociceptors are categorized as silent, displaying no basal mechanical sensitivity and responding only when the supporting tissue is damaged or inflamed (Gold and Gebhart, 2010). Nociceptors are also classified as C or Aδ type based on their axonal diameter and the degree of myelination, both factors influencing the speed of conduction of electric signals. C-type nociceptors are slowly conducting and unmyelinated while Aδ nociceptors are thinly myelinated and have conduction speeds of 3–10 m/s. Moreover, nociceptors differentially express a variety of biochemical markers, underscoring their functional heterogeneity (Gold and Gebhart, 2010; Laing and Dhaka, 2016).
Our understanding of transduction and encoding mechanisms in primary sensory neurons, including nociceptors, has advanced greatly in the last two decades (Basbaum et al., 2009; Dubin and Patapoutian, 2010; Gold and Gebhart, 2010) (see Chapters 2–52345). The detection of stimuli by nociceptor neurons is based on membrane signaling molecules which convert the stimulus energy into an allosteric molecular change, leading to the gating of membrane ion channels and graded depolarization (i.e., generator potential) of the nerve terminal. In nociceptors, most transduction molecules are ion channels that are directly gated by the stimulus or by intracellular messenger systems activated by a variety of chemical substances. Several classes of ion channels have been associated with transduction of the various forms of energy and the production of generator potentials at nociceptor nerve terminals, with transient receptor potential (TRP) channels playing a critical role in the detection of thermal stimuli (Dhaka et al., 2006; Belmonte et al., 2009; Laing and Dhaka, 2016). TRP channels are nonselective cation channels; their opening results in influx of sodium and calcium into the nerve ending, which will depolarize.
In this chapter, we highlight cellular and molecular mechanisms involved in the transduction of thermal (warm and cold) stimuli by nociceptors and their changes in situations that result in the amplification of painful responses. Additional information about the transduction of thermal stimuli can be found in Chapters 2–5, 7, and 8234578. It should be emphasized that, in addition to triggering avoidance behaviors, thermal signals give rise to reflex autonomic responses that are critical for thermoregulation and other homeostatic functions such as energy balance (Romanovsky, 2007).
Section snippets
Neural pathways for pain and thermal sensations
Nociceptive and thermal information from the periphery reaches the spinal cord and the brainstem to contact second-order neurons. These sensory afferents terminate in the superficial spinal (and trigeminal) dorsal horn. Some lamina I spinothalamic neurons are highly specific for thermoreceptive stimuli, with cold-sensitive neurons found more frequently than warm-sensitive neurons (Han et al., 1998; Craig et al., 2001).
From there, the neural message is conveyed by the crossed spinothalamic tract
Transduction of heat stimuli by nociceptors
Application of noxious heat to small spots on the human skin evokes pain with a burning or stinging quality that increases in magnitude with the intensity of the stimulus. The detection of noxious heat is mediated by activation of a specialized subset of skin nociceptors. The response to noxious heat is characterized by a sharp first pain sensation, with a latency of around 400 ms and thresholds around 43–45°C (Campbell and LaMotte, 1983). This first pain is thought to be transmitted by
Mechanism of cold transduction
Cooling the skin evokes different sensations depending on the intensity, rate of temperature change, and size of the receptive area stimulated (Davis and Pope, 2002; Belmonte et al., 2009). Small temperature decreases are generally perceived as pleasantly cool. They involve the activation of cold thermoreceptors (Hensel, 1974). In healthy individuals, at skin temperatures below 15–20°C cold becomes an unpleasant sensation, turning progressively more painful as temperature drops. Cooling, below
Thermal hyperalgesia and thermal allodynia
Allodynia is defined as pain in response to a nonnociceptive stimulus (Loeser and Treede, 2008). The term allodynia derives from the ancient Greek words allos (other) and odynia (pain) and was intended to emphasize a change in the quality of the sensation (e.g., innocuous touch becoming painful) (Fig. 6.1). Dynamic mechanic allodynia is thought to originate in sensitized low-threshold Aβ fibers that gained access to central nociceptive processing. In the case of thermal stimuli, it refers to
Mechanism of heat hyperalgesia
Skin injury (e.g., a burn) or inflammation causes innocuous heat to become painful. Hypersensitivity to heat is also a prominent sign in systemic inflammatory disorders such as rheumatoid arthritis. In addition, thermal allodynia and hyperalgesia are common symptoms in patients after injury to the somatosensory nervous system, a condition known as neuropathic pain (Colloca et al., 2017). Conditions associated with neuropathic pain include peripheral nerve injuries, chemotherapy, postherpetic
Cold perception and cold allodynia
Cold allodynia and cold hyperalgesia are common signs in various neuropathic conditions, including peripheral neuropathies caused by chemotherapeutic agents (e.g., oxaliplatin and paclitaxel), posttraumatic nerve injury (e.g., complex regional pain syndrome type 2, amputation), and also as a consequence of a stroke (e.g., central poststroke pain) (Jensen and Finnerup, 2014). Cold-evoked pain is also a common occurrence in diabetic neuropathy. It is frequent in ciguatera, caused by consumption
Molecular mechanisms of cold allodynia and hyperalgesia
It is unresolved which cellular alterations lead to cold allodynia and hyperalgesia in different clinical conditions. Several mechanisms have been proposed, including peripheral sensitization of nociceptors and central disinhibition (reviewed by Belmonte et al., 2009; Jensen and Finnerup, 2014). Molecular studies in preclinical models are also inconclusive and the evidence in favor of different receptors and pathways is still fragmentary (Lolignier et al., 2016). It is important to stress that
Neural plasticity and pathologic pain
Painful events are powerful inducers of learning and remembering. Supraspinal structures and circuits play a major role in the modulation and representation of the pain experience (Apkarian et al., 2005, Apkarian et al., 2011). Persistent pain may lead to functional and structural plasticity at various levels of the pain axis (May, 2008). Synaptic plasticity is well established in nociceptive pathways and participates in the mechanisms of pathologic pain (Sandkuhler, 2009; Luo et al., 2014).
Learning from mutations
Genetic factors strongly contribute to pain sensitivity, susceptibility to developing chronic pain disorders, and the response of individual patients to analgesics (Sexton et al., 2018). A number of mutations in the SCN9A gene, encoding the TTX-sensitive voltage-gated sodium channel Nav1.7, have been identified as critical cellular substrates for several heritable pain syndromes (Hoeijmakers et al., 2012; Lampert et al., 2010). These and other mutations can be consulted at the Online Mendelian
Treatment of hyperalgesia and allodynia
Adequate pain treatment is central to the management of many diseases and injuries. Unfortunately, current treatments of chronic pain symptoms are unsatisfactory in many cases, especially in neuropathic injuries. In addition, most treatments have significant adverse side-effects that limit their utility. As already mentioned, hyperalgesia and allodynia are clinical terms and do not provide any insight to the mechanisms underlying the pain condition. Treatment should always take into
Conclusions and future directions
Our knowledge about the cellular and molecular mechanisms causing thermal hyperalgesia and allodynia in human subjects is still very fragmentary. In order to develop more effective therapies, a better understanding of the underlying pathophysiologic mechanisms involved in thermal hypersensitivity following inflammation and nerve injury is needed.
As indicated, nociceptors are very heterogeneous and their relative contribution to specific forms of pain hypersensitivity is currently unknown.
Acknowledgments
The author acknowledges funding from the Spanish MICINN projects SAF2016-77233-R and PRX16/00188, co-financed by the European Regional Development Fund (ERDF) and the “Severo Ochoa” Programme for Centres of Excellence in R&D (ref. SEV-2017-0723).
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2021, NeuroscienceCitation Excerpt :Spontaneous and evoked pains clinically characterize NP. It can occur as a dysfunction in the peripheral or the central nervous systems (Viana, 2018). NP can be characterized by allodynia or hyperalgesia (Sandkühler, 2009; Jensen and Finnerup, 2014).
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2021, ToxiconCitation Excerpt :From that point, the signal is carried by the spinothalamic tract and decoded in regions of the pain matrix, which include thalamus, sensorimotor cortex, insular cortex and anterior cingulate cortex (Mertens et al., 2015; Von Hehn et al., 2012). The circuits that induce hyperalgesia are not well understood, studies in preclinical experimental models are inconclusive and the evidence in favor of different receptors or pathways is still fragmentary (Lolignier et al., 2016; Viana, 2018). One of the possible mechanisms include the increase in the expression of neurotrophic factors that can alter the excitability of nociceptors resulting in hyperalgesia (Ottestad and Angst, 2012).
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2021, Neuroscience LettersCitation Excerpt :Neuropathic pain (NP) can be either spontaneous or evoked. Either primary malfunction of the peripheral or central nervous systems may cause NP [14]. It can be manifested as allodynia or hyperalgesia [15,16].
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2021, Experimental Cell ResearchCitation Excerpt :Inflammatory pain is common in clinical situations, and is the main type of chronic pain that afflicts patients [1]. Characterized by hyperalgesia and allodynia, inflammatory pain was arisen from tissue damage and harmful stimulation [2,3]. Of note, inflammatory pain affects patient's daily life through changing usual functions and activities that results in motor disabilities, and may also affect the prognosis of patient [4].
Thermal Hyperalgesia and Mechanical Allodynia Elicited by Histamine and Non-histaminergic Itch Mediators: Respective Involvement of TRPV1 and TRPA1
2020, NeuroscienceCitation Excerpt :We believe that intraplantar injection of the pruritogens tested presently elicits itch, based on previous studies reporting that intraplantar injection of the itch mediator, serotonin (5-hydroxytryptamine, 5-HT) elicited biting behavior in rats (Klein et al., 2011b) and mice that was reduced by a μ-opiate receptor antagonist (Hagiwara et al., 1999), consistent with biting being an itch-related behavior. The thermal hyperalgesia and mechanical allodynia elicited by histamine, chloroquine, BAM8-22 and SLIGRL are indicative of primary hyperalgesia that occurs rapidly via peripheral sensitization of pruriceptors by local inflammatory mediators (LaMotte et al., 1991; Simone, 1992; Treede et al., 1992; Woolf, 1995; Petho and Reeh, 2012; Viana, 2018). Pruriceptors for non-histaminergic itch are thought to be polymodal C-fiber nociceptors, while those for histaminergic itch are mechano-insensitive C-fibers (Schmelz et al., 1997; Johanek et al., 2008; Namer et al., 2008).