Advances in understanding nociception and neuropathic pain

Journal of Neurology, Oct 2017

Pain results from the activation of a subset of sensory neurones termed nociceptors and has evolved as a “detect and protect” mechanism. However, lesion or disease in the sensory system can result in neuropathic pain, which serves no protective function. Understanding how the sensory nervous system works and what changes occur in neuropathic pain are vital in identifying new therapeutic targets and developing novel analgesics. In recent years, technologies such as optogenetics and RNA-sequencing have been developed, which alongside the more traditional use of animal neuropathic pain models and insights from genetic variations in humans have enabled significant advances to be made in the mechanistic understanding of neuropathic pain.

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Advances in understanding nociception and neuropathic pain

Advances in understanding nociception and neuropathic pain Ewan St. John Smith 0 0 Department of Pharmacology, University of Cambridge , Tennis Court Road, Cambridge CB2 1PD , UK 1 Ewan St. John Smith Pain results from the activation of a subset of sensory neurones termed nociceptors and has evolved as a “detect and protect” mechanism. However, lesion or disease in the sensory system can result in neuropathic pain, which serves no protective function. Understanding how the sensory nervous system works and what changes occur in neuropathic pain are vital in identifying new therapeutic targets and developing novel analgesics. In recent years, technologies such as optogenetics and RNA-sequencing have been developed, which alongside the more traditional use of animal neuropathic pain models and insights from genetic variations in humans have enabled significant advances to be made in the mechanistic understanding of neuropathic pain. Chemogenetics; Neurocircuitry; Neuropathic pain; Nociceptor; Optogenetics; Voltage gated sodium channel (NaV) Introduction Nociception is the neural process of encoding noxious stimuli, whereas pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage [ 1 ]. Nociception has been described in a variety of organisms, from the nematode worm Caenorhabditis elegans through to humans, but the case for pain is less clear. Although humans and likely all mammals experience negative emotion, this is considered unlikely in C. elegans, but the case for certain organisms, especially fish, is more contentious [ 2–4 ]. Numerous reviews have been written about different aspects of pain, from its molecular basis [ 5–10 ] and genetic mechanisms [ 11–13 ] to its pharmacological treatment [ 14–16 ]. The purpose of this review is to discuss how recent insights into pain mechanisms from pre-clinical research may lead to breakthroughs in our understanding, and hopefully treatment, of chronic pain. Chronic pain is usually defined as regularly occurring pain over a period of several months and it has a prevalence of ~11–19% of the adult population [ 17–19 ]. Broadly speaking, chronic pain can be split into two categories, inflammatory pain and neuropathic pain. Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system and a systematic review of epidemiological studies estimates the prevalence of neuropathic pain to be 6.9–10% [ 20 ]. The need for novel therapies to treat neuropathic pain is demonstrated by the analysis of analgesia success. A 2006 report on chronic pain in Europe identified that 64% of those taking prescription medicine found that their pain medication was at times inadequate, and of the 48% of chronic pain sufferers not taking pain medication, 14% had stopped due to side effects [ 18 ]. To develop new treatments for neuropathic pain, it is important to first understand the circuitry of pain: how is pain triggered and how is that information transmitted to the central nervous system? To do this, it is necessary to understand how nociceptors function. Nociceptors: transducers of pain The human body is equipped with different types of sensory neurones and nociceptors are the subset that function as the primary unit of pain, being equipped with receptors and ion channels that enable the detection of stimuli that have potential to cause damage. When a noxious stimulus activates an ion channel on a nociceptor, for example proton activation of acid-sensing ion channels (ASIC), cation influx depolarises the nociceptor producing a receptor potential. If the receptor potential is of sufficient magnitude to reach the activation threshold for voltage-gated Na+ channels (NaV), it will trigger action potential generation and transmission of a pain signal to the spinal cord [ 2, 5, 21 ]. In recent years, many new techniques have been developed in pre-clinical research that have accelerated our progress in understanding how nociceptors work and provide tantalising glimpses at their clinical utility. Indeed, such work is essential for both identifying potential new painkiller targets and the developing novel biological treatments for neuropathic pain. Nociceptor functionality Anatomical and in vivo/in vitro electrophysiological data show that some nociceptors are myelinated Aδ-fibres and that others are unmyelinated C-fibres, different subsets of which are sensitive to a different range of stimuli, most being polymodal, but others responding to a narrower range of stimuli [ 2, 5 ]. Recent developments in transgenic mouse and imaging technology have led to elegant in vivo experiments using the genetically encoded Ca2+-indicator GCaMP [ 22–24 ], the fluorescence intensity of which is proportional to intracellular [Ca2+]. In contrast to electrophysiological studies, which suggest a predominantly polymodal nociceptor phenotype, some GCaMP studies have (...truncated)


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Ewan St. John Smith. Advances in understanding nociception and neuropathic pain, Journal of Neurology, 2017, pp. 1-8, DOI: 10.1007/s00415-017-8641-6