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)