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Primer group to metazoans derived from ganglia. Axons from the nociceptive
a distant common ancestor. The neurons output to neural circuits in the
Nociception presence of nociception genes in these
distant relatives of metazoans suggests
dorsal horn of the spinal cord, which
in turn transmit the inputs to the brain
the intriguing possibility the molecular through ascending neuronal pathways.
W. Daniel Tracey, Jr.1,2,* mechanisms used by nociceptors for It is in the brain where pain perception
the detection of damaging stimuli may occurs downstream of the nociceptive
Nociception, the sensory mechanism have been in use by organisms for input. Nociception and pain are thus
that allows animals to sense and the avoidance of damage even before separable processes: pain can occur in
avoid potentially tissue-damaging nervous systems evolved. the absence of nociceptive input and
stimuli, is critical for survival. This In this Primer, I provide a brief nociception can occur in the absence
process relies on nociceptors, which introduction to nociception systems of pain. An example of the latter is
are specialized neurons that detect across the animal kingdom with represented by the spinal reflexes that
and respond to potentially damaging particular attention to the cellular and occur in response to nociceptive inputs
forms of energy — heat, mechanical molecular mechanisms involved in (such as the withdrawal of a hand
and chemical — in the environment. the detection of noxious temperature, from a hot object) without the need for
Nociceptors accomplish this task noxious force, and noxious chemicals. descending control by the brain.
through the expression of molecules When the signals from the periphery
that function to detect and signal Nociceptors and the stimuli they reach the brain, the quality of the painful
the presence of potential harm. detect sensation is related to the type of neuron
Downstream of the nociceptive Various physical stimuli in the that has been activated. With noxious
sensory input, the neural signals trigger environment have the potential to heat stimuli the intensity of the pain
protective (nocifensive) behaviors, and damage organisms and are sensed correlates with the strength of activation
the sensory stimuli that reach the brain by nociceptors. Whether or not an of slowly conducting unmyelinated
may be perceived as painful. organism can detect a particular C-fibers that rapidly adapt to the heat
Nociception has been described in stimulus using its nociceptors is stimulus, but with prolonged heat stimuli
diverse animal taxa and is likely to be affected by its evolutionary history, the heat pain is also carried by rapidly
an ancient sensory system that may niche it inhabits, and by its adaptations conducting thinly myelinated axons
have existed in a metazoan ancestor to that niche. Nociceptors can be (A- fibers) that show more prolonged
that pre-dated the divergence of activated by strong heat, intense cold, and non-adapting responses. Both the
protostomes and deuterostomes. harsh mechanical stimuli, and a variety A-fibers and the C-fibers can also be
Evidence for this can be found in of chemical stimuli. A vast literature mechanically sensitive and are involved
the use of evolutionarily conserved exists on mammalian nociceptors, in the transmission of mechanical pain
signaling pathways for nociception which have been classified according (Table 1). Many fibers are polymodal and
by insects, nematode worms and to conduction velocity (fast or slow), can be activated by both high threshold
mammals. Homologs of molecules diameter, amount of myelination, mechanical and thermal stimuli.
critical for nociception — such as and the types of stimuli to which In peripheral tissues, such as the
transient receptor potential (TRP) they respond. Nociceptors may be skin, the axons of the nociceptive
ion channels — have even been polymodal and activated by several neurons form a complex and highly
found in the sequenced genomes of classes of noxious stimulus (i.e. heat, branched plexus beneath the epidermis
choanoflagellates. Although these mechanical and chemical stimuli), (Figure 1A–1C) where they are
single-celled and colonial organisms or they may be more specialized in ensheathed by peripheral glia known
lack a nervous system, they still their responses. The cell bodies of as Schwann cells. The terminal axons
possess genes used for neural the mammalian nociceptor neurons lose their Schwann cell ensheathment
transmission and neuronal excitability are found in the peripheral nervous as they penetrate the keratinocyte
and are believed to represent a sister system in dorsal root and trigeminal layer to become so called ‘naked’

Table 1. Nociceptive neurons and molecules in genetically tractable organisms.

Nociception Genetic models Neuronal detectors Candidate Candidate molecular Candidate molecular
modality Mouse, fly, worm molecular sensors: sensors: fly sensors: mouse
worm
Noxious Mouse, fly, worm C-fiber, A-δ, cIVda, ? Painless, dTRPA1, TRPV1–4, anoctamin,
heat AWC, AFD anoctamin TREK-1
Noxious Mouse, fly, worm C-fiber, A-δ, cIVda, PVD DEGT-1/MEC-10 PPK/BBA, Piezo TRPA1, TRPV4, TREK-1
mechanical Possibly Piezo-1/-2, TMCs
Noxious Mouse, fly, worm C-fiber, A-δ, GRN1, Odorant receptors, Painless, dTRPA1 TRPA1, TRPV1
chemical PVD, ASH OSM-9
Noxious Mouse, fly, worm C-fiber, cIIIda, PVD TRPA1 TRPM, PKD2, TRPM8/TRPA1
cold NOMP-C
1
GRN, gustatory receptor neuron.

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of escape because the speed of

movement with larval rolling is nearly
twice as fast as the speed of larval
crawling. Either noxious heat or noxious
mechanical stimuli can trigger rolling
and we have found that attacks from
a natural enemy of the fly larvae, the
parasitic wasp Leptoplina boulardi, also
trigger rolling. The nociceptive sensory
neurons in the fly larvae are known
as class IV multidendritic arborization
(cIVda) neurons (Figure 2). As the name
suggests, these cells possess highly
arborizing dendrites that run along the
extracellular matrix at the basolateral
surface of the single layer of larval
epidermal cells. The epidermal cells
form a tight barrier to the outside world
through cell–cell adhesions and through
the secretion of cuticular proteins
at each of the three larval stages of
development. The dendrites are found
on the apical side of the basal lamina
and they have also been found to pass
through epidermal cells, which embrace
the dendrites as they do so. Thus, these
dendrites are well situated to detect
the various insults in the environment
that might result in a compromised or
damaged epidermal barrier, such as the
penetration of a wasp ovipositor.
The nematode worm C. elegans
possesses a set of polymodal
nociceptive neurons that appear quite
Figure 1. Nociceptive sensory endings in mouse skin. similar to the multidendritic neurons of
(A, B) Nociceptive MrgD+ nerve endings visualized by sparse genetic tracing in MrgD- the fly larvae. The sensory dendrites of
CreERT2;Rosa-iAP mice in back (A) and glabrous (B) skin (images courtesy of William Olson and
these PVDL and PVDR neurons have
Wenqin Luo, University of Pennsylvania). (C) Peptidergic nociceptive endings in skin, genetically
labeled in a CGRP-alpha-GFP knock-in mouse (McCoy et al. (2013); image courtesy of Mark Zylka the appearance of a candelabra and
and Bonnie Taylor-Blake, UNC Chapel Hill). Scale bars in all panels, ~100 m. have been dubbed ‘menorah cells’
after the traditional Hebrew candle
nerve endings. The historical view has in mammals, such as rats (Rattus holder. The menorah cells have been
been that the sensory function of these norvegicus), laboratory mice (Mus found to play a role in detecting harsh
nociceptive endings is completely musculus), non-human primates, touch and noxious cold temperatures.
autonomous without the need for and humans. However, a growing Interestingly, a recent report has
specialized sensory receptor cells. number of studies have been carried shown that noxious cold detection in
However, emerging evidence implicates out in invertebrate organisms, such fly larvae may be mediated by class III
a potential role for keratinocytes as Drosophila melanogaster and multidendritic neurons (cIIIda), which
in transmitting or facilitating the Caenorhabditis elegans. Nociceptors nicely parallels the functions of menorah
transmission of noxious signals to have also been found in annelid worms cells. A distinction from worms,
the nerve endings. Optogenetic (Hirudo medicinalis) and molluscs however, is that the cIIIda fly cells are
and chemical genetic activation of (Aplysia californica). responsive to gentle touch stimuli.
keratinocytes can directly initiate Work in my laboratory has been Another class of nociceptor — ASH —
nociception behaviors in mice. As focused on studies of nociception is found in the nose of the worm and
well, expression of TRPV channels has using Drosophila larvae, which senses potentially damaging chemical
been found in keratinocytes and these display a stereotyped pattern of stimuli, such as hyperosmolarity, heavy
channels may play a role in the sensing escape locomotion that is triggered metals, and other toxic compounds.
of noxious stimuli by these cells. by nociceptive stimuli. This pattern
of locomotion causes larvae to rotate Sensitization, hyperalgesia, and
Invertebrate nociceptors around the long body axis and to efferent function of nociceptors
The vast majority of the work on roll across the substrate. Rolling Vertebrate nociceptors not only
nociception has been performed locomotion is an effective means carry afferent information to the

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central nervous system but also

locally transmit information in the
periphery. The nociceptive terminals
of C-fibers in the skin have vesicles
containing neuropeptides such as
substance P and calcitonin gene
related peptide that are released upon
stimulation to cause physiological
effects in the surrounding tissue. The
combined effects produce so-called
‘neuroinflammation’. The well-known
redness and swelling or ‘flare’ that
can be seen in the skin surrounding a
localized heat or mechanical injury is
the result of neuroinflammatory effects
on the local vasculature. Swelling is
due to local release of blood plasma
(plasma extravasation) and redness
is due to local vasodilation, which
provides increased blood flow to the
site of injury. The flare that occurs
following nociceptor activation covers
a significantly larger area than the Figure 2. Nociceptive neurons in living third instar Drosophila larvae.
site of the stimulus itself and is likely Composite confocal micrograph of two adjacent ddaC class IV multidendritic neurons in third
instar Drosophila larvae labeled with mCD8::GFP (image courtesy of Stephanie Mauthner, Univer-
due to a peripheral axon reflex where sity of Indiana). Scale bar, ~ 50 m.
the action potentials of the stimulus
spread into adjacent branches of the Molecular mechanisms of present in vivo may be absent from
nociceptor neuron. Nearby neurons nociception cultured neurons. Another caveat with
may also be recruited in this spreading, In order for nociceptive neurons to the use of cultured neurons is that gene
as the size of the flare can be larger transmit the presence of harmful expression profiles are known to differ
than the typical receptive field of a energy to the central nervous system, from those that are found in vivo.
nociceptor. molecules present in the nerve endings
Following injury the nociceptors must detect these stimuli. The process Thermal nociception
themselves may become sensitized by which harmful energy is converted In mammalian nociceptors, noxious
by the release of proinflammatory into ionic currents is known as sensory heat of more than 40oC activates the
mediators, such as prostaglandins, transduction. Conduction occurs heat-sensitive C-fibers and heat of more
bradykinin, substance P, extracellular downstream of transduction, in the than 52oC activates A-fibers. A great
ATP and protons. With sensitization, form of action potentials that are carried deal of excitement in the nociception
nociceptors can become activated by by the nerve fibers, and results in the field came with the discovery that
normally innocuous stimuli (a process release of neurotransmitters in the members of the TRP family of ion
known as allodynia) and activated dorsal horn. Transduction is believed to channels could be activated by
even more strongly by painful stimuli occur in the naked nerve endings, but heating, with thresholds that were
(a process known as hyperalgesia). In because these nerve endings are buried very well matched to the sensory
addition, transmission from the non- within tissues such as the epidermis thresholds of these fibers. This was first
nociceptive fibers that are responsive it has not been possible to directly demonstrated with the discovery of
to innocuous stimuli, such as gentle observe the ionic currents of nociceptor TRPV1, the long sought-after receptor
warming or gentle touch, may be transduction. Instead, much of what is for capsaicin (the spicy ingredient of
perceived as painful. The latter is likely known comes from electrophysiological chili peppers): not only could the TRPV1
due to neuromodulatory changes in recordings of cultured neurons. These channel be activated by capsaicin,
the spinal cord circuitry that occur recordings allow for direct access and but it could also be directly activated
following the injury. This allows the measurements of ion channels present by heat in the noxious range. This
normally innocuous inputs to gain in the neuronal membrane of the cell observation provided a potential
access to the ascending pathways soma and in short neurites that develop molecular explanation for how thermal
that normally carry stimuli from the in culture. In many cases, the molecules nociceptors could be activated by both
nociceptors to the brain. Interestingly, that are present in the cultured neurons noxious heat and by capsaicin (which
nociceptive sensitization occurs in both can be shown to also be present at is why chili peppers elicit a sensation
invertebrate and vertebrate nociceptors, the peripheral terminals so a great deal of burning pain). Additionally, other
with evidence for a conserved pathway has been learned from these studies. mammalian TRP channels have been
involving the Hedgehog signaling However, given that transduction found to be activated by temperatures
pathway and the substance-P-like molecules could be locally synthesized in the noxious range (i.e. TRPV2, TRPV3
tachykinin peptides. in the periphery, important factors and TRPV4).

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The rigorous test of the hypotheses detection of noxious force. By analogy encoded by products of the pickpocket
that these channels might explain the to other mechanosensory systems, the (ppk) and balboa (bba/ppk26) genes
detection of noxious heat in vivo came working hypothesis in the field is that shows very specific expression in
with the generation of mutant mice for mechanical nociception requires the the multidendritic nociceptors. This
each of the genes. While removal of action of force-sensing ion channels. channel is required for mechanical
TRPV1 caused marked defects in the These putative mechanosensory nociception responses but not for
ability of mice to detect capsaicin and channels are postulated to be present thermal nociception responses. The
also a reduction in thermal hyperalgesia in the naked sensory endings of the Drosophila piezo gene is also required
triggered by inflammation, substantial nociceptors. Direct measurements for mechanical nociception responses
baseline thermal nociception remained. of the force-gated ionic currents of in a pathway that is parallel to the
Further, mutation of TRPV2, TRPV3 and sensory endings that are buried within ppk/bba pathway. Interestingly, the fly
TRPV4 has modest or no effect on the tissues such as the epidermis have Piezo channel generates mechanically
noxious heat responses of nociceptor not been possible. Thus, as with activated currents when expressed
neurons. Thus, while TRP channels do thermal nociception, much of what is in heterologous cells, suggesting that
play an important role in the detection known about the mechanical activation it is directly involved in converting
of noxious heat, other pathways remain properties of mammalian nociceptors mechanical energy into ionic currents
in their absence. Additional candidate comes from electrophysiological in this nociception pathway. As in flies,
ion channel molecules for modulating recordings made from cultured neurons. DEG/ENaC/ASIC channels (DEGT-1 and
noxious heat detection in mammals Several distinct mechanically gated MEC-10) are important for mechanical
include the chloride-permeable channel currents are present in the soma nociception in C. elegans, where they
TMEM16A/anoctamin and the two-pore of these neurons, but how these are required for sensing harsh touch
potassium channels TREK1, TREK2 and currents relate to detection of noxious detected by the PVD nociceptive
TRAAK. mechanical stimuli in vivo remains neuron. DEG/ENaC/ASIC channel family
Invertebrate detection of noxious largely undetermined. Mechanically members (ASIC1–3) are expressed in
heat also requires TRP channels. activated currents in nociceptors can neurons of the mammalian dorsal root
In Drosophila larvae and adult flies, also inhibit nociceptor firing and this ganglion, but mice with mutations in
the TRPA channel family members may contribute to the high threshold for these genes do not show defects in
painless and dTRPA1 have been found mechanical pressures needed to trigger mechanical nociception responses.
to play a role in thermal nociception. action potentials. Such inhibitory, One mechanism for mechanical
Painless and TRPA1 each have both mechanically activated potassium nociception that is little discussed
heat-activated and heat-insensitive currents are mediated by TREK and involves the physical breakage of
protein isoforms. The thermal activation KV1.1 channels. Candidate molecules nociceptive nerve endings that can
properties of TRPA channels are quite that are responsible for mediating the occur following the noxious insult. For
plastic in evolution, as the vertebrate depolarizing currents that activate the instance, we have found that the fine
TRPA channels can be activated by nociceptors in response to force include dendrites of the nociceptive neurons
heat (as in snakes) or by noxious cold TRP channels (i.e. TRPA1 and TRPV4) in the Drosophila larva are locally
(as in mice). The evolutionary plasticity and Piezo channels. In addition, a disrupted upon penetration of the
of the TRPA channels is also seen in newly identified class of ion channels, epidermis by the ovipositor of parasitoid
the invertebrate lineage, as C. elegans known as TMC family ion channels, wasp females. When a neurite is broken
TRPA channels play a role in noxious are candidate mechanotransduction in this way, a strong depolarization of
cold avoidance that is distinct from molecules in nociceptors. the arbor is expected and is likely to
the role in heat sensing that has been Studies in vertebrates have not result in a train of action potentials. In
reported in flies. As in mammals, a yet revealed a role for Piezo family addition to the cell-autonomous effects
Drosophila anoctamin channel has been channels in mechanical nociception. associated with physical damage to
implicated in thermal nociception. A Known phenotypes of piezo2 mouse the neurites themselves, disruption of
genome-wide RNAi screen for genes mutants include profound defects in cells surrounding the endings releases
that protect adult flies from paralysis gentle touch responsive neurons and factors that bind to receptors on the
upon exposure to noxious heat has proprioception, while piezo1 mutants neurite and activate it. The classically
identified hundreds of genes. Screens have impaired lung inflation. As cited example involves the release
performed in larvae have found over 40 well, bi-allelic disruption of piezo2 in of ATP from damaged cells and the
nociception genes, many of which are human patients affects proprioception activation of ATP-gated ion channels
distinct from those found in the adult and touch tasks without affecting (i.e. P2X3) present on nociceptive
screens. In addition, a growing number mechanical pain. Analyses of piezo1 endings.
of molecules have been implicated in piezo2 double mutant nociceptors
nematode nociception. could prove to be informative regarding Chemical nociception
mechanisms of mechanical nociception. The general function of nociceptors
Mechanical nociception Invertebrate mechanical nociception in protecting organisms from tissue
Relative to our understanding of the relies on ion channels of the degenerin/ damage includes the ability of
molecular mechanisms for the detection epithelial sodium channel/acid sensing these sensory neurons to detect
of noxious heat in mammals very ion channel family (DEG/ENaC/ASIC). potentially damaging chemicals. As
little is known of the mechanisms for In flies, a heteromeric ion channel such, nociceptors of various animals

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and fish. inflammatory actions of environmental irritants Zhong, L., Bellemer, A., Yan, H., Honjo, K.,
and proalgesic agents. Cell 124, 1269–1282. Robertson, J., Hwang, R.Y., Pitt, G.S., and
Braz, J., Solorzano, C., Wang, X., and Basbaum, A.I. Tracey, W.D. (2012). Thermosensory and
Future directions (2014). Transmitting pain and itch messages: a non-thermosensory isoforms of Drosophila
Much of what is known from studies contemporary view of the spinal cord circuits melanogaster TRPA1 reveal heat sensor domains
that generate gate control. Neuron 82, 522–536. of a thermoTRP channel. Cell Rep. 1, 43–55.
of nociception comes from studies in Burrell, B.D. (2017). Comparative biology of pain:
genetically tractable model organisms what invertebrates can tell us about how
1
and, while much has been learned, nociception works. J. Neurophysiol. Linda and Jack Gill Chair in Neuroscience,
http://dx.doi.org/10.1152/jn.00600.2016. Gill Center for Biomolecular Science, Indiana
much remains to be understood. Caterina, M.J., and Julius, D. (2001). The vanilloid University, Bloomington, IN 47401, USA.
Important questions remain. For receptor: a molecular gateway to the pain 2
pathway. Annu. Rev. Neurosci. 24, 487–517. Department of Biology, Indiana University,
instance, what are the TRP-channel- Chiu, I.M., Barrett, L.B., Williams, E.K., Bloomington, IN 47401, USA.
independent mechanisms of thermal Strochlic, D.E., Lee, S., Weyer, A.D., Lou, S., *E-mail: [email protected]

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