Nociceptors: thermal allodynia and thermal pain

Abstract

The sensation of pain plays a vital protecting role, alerting organisms about potentially damaging stimuli. Tissue injury is detected by nerve endings of specialized peripheral sensory neurons called nociceptors that are equipped with different ion channels activated by thermal, mechanic, and chemical stimuli. Several transient receptor potential channels have been identified as molecular transducers of thermal stimuli in pain-sensing neurons.

Skin injury or inflammation leads to increased sensitivity to thermal and mechanic stimuli, clinically defined as allodynia or hyperalgesia. This hypersensitivity is also characteristic of systemic inflammatory disorders and neuropathic pain conditions. Mechanisms of thermal hyperalgesia include peripheral sensitization of nociceptor afferents and maladaptive changes in pain-encoding neurons within the central nervous system.

An important aspect of pain management involves attempts to minimize the development of nociceptor hypersensitivity. However, knowledge about the cellular and molecular mechanisms causing thermal hyperalgesia and allodynia in human subjects is still limited, and such knowledge would be an essential step for the development of more effective therapies.

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).