Pain Transduction: Gating and Modulation of Ion Channels

Abstract

The sensation of pain informs us that potentially or actually damaging stimuli (noxious stimuli) are impinging on our bodies. All animals, and even many single-celled organisms that could scarcely be dignified by the name animal, show some form of avoidance reaction in response to noxious stimuli. Pain has therefore been a feature of many forms of life since early in evolution, and we would expect pain to be a highly evolved and complex sensation, responsive to a multitude of harmful stimuli, either those present in the external environment or those generated within the organism itself. The word “pain” causes some difficulties because it covers a multitude of quite separate concepts. Pain refers to the processes involved in detection of the physical effects of an injury (e.g. the pain of a fracture); to the perceptual and emotional reaction to an injury (the “feeling” of pain); and to similar sensations experienced in response to a purely emotional event (e.g. the pain of parting). Sherrington, in 1906, removed the emotional connotations of the word “pain” from the physical process of detection of a painful stimulus by coining the word “nociceptor” (a receptor for noxious stimuli) to refer to those primary sensory neurons that are activated by stimuli that we would regard as painful. The existence of nociceptors as a separate class of sensory neurons was doubted for many years, and it was proposed instead that the sensation of pain could result from the strong stimulation of sensory receptors responsible for detecting nonpainful stimuli, an idea which was given support by the discovery of second-order neurons in the deeper layers of the dorsal horn of the spinal cord which respond to a wide range of stimuli, both nonnoxious and noxious. However, Ed Perl in 1969 recorded directly from primary afferent nerve fibers and was able to demonstrate clearly that a separate class of primary sensory afferents responding only to high-threshold stimulation did indeed exist and had properties quite distinct from those of receptors responding to nonnoxious stimulation. Thus, the existence of a distinct class of nociceptive neurons, as postulated by Sherrington, was finally confirmed. Nociceptors, like all somatic sensory neurons, are “long” neurons in which the sensory terminal must be depolarized and action potentials elicited in order to communicate to the distant central synaptic terminals. The generator current activated in nociceptive nerve terminals by all noxious stimuli must therefore be inward, as it is in all somatic sensory neurons. In many other respects, however, nociceptive neurons differ from other sensory neurons, although most of the functional differences are readily explicable in terms of the tasks that nociceptors are designed to carry out. Most obviously, a painful stimulus is, almost by definition, large in magnitude, so the cellular amplification pathways that form a prominent part of (for instance) olfactory and visual sensory transduction are not often seen in nociceptive transduction—most stimuli, in fact, act directly to gate an ion channel. Our current understanding of ion channels important in nociception is discussed below. Secondly, while most sensory receptors respond with exquisite sensitivity to only a single sensory modality (for instance, a narrow band of wavelengths of light in the case of visual receptors), nociceptors are typically polymodal, responding to a wide range of stimuli, which may include strong mechanical stimuli, heat, extreme cold, and a range of noxious chemical stimuli. Polymodal behavior makes sense in the context of pain, where the organism will be more concerned with detecting a noxious stimulus and taking appropriate avoiding action, rather than with analyzing the precise nature of the stimulus. Finally, in all other sensory receptors, adaptation is seen in response to the maintained presentation of a stimulus, a property that enables the receptors to operate over a wide range of stimulus intensities. The response of nociceptors, in contrast, typically increases, or sensitizes, in response to a prolonged or intense stimulus, a property that ensures that a noxious stimulus is not ignored by the organism. Our current understanding of the molecular basis of sensitization is discussed below. Keywords: Action Potential; Adaptation; Afferent Nerve; Depolarization; Efferent Nerve Fiber; Hyperalgesia; Ion Channel; Neuropathic Pain; Nociceptor; Primary Sensory Neuron; Sensitization; Transduction