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The development of nociceptive circuits

Key Points

  • Newborn infants show strong pain behaviour, but the nature of this pain is poorly understood and has, historically, been undertreated. The study of the development of nociceptive pathways shows that infant pain involves functional signalling pathways that are not found in the mature nervous system of healthy individuals. This review focuses on the underlying organization and strengthening of nociceptive circuitry in the dorsal horn during the first postnatal weeks and shows how this circuitry might be altered by sensory inputs in early life.

  • Peripheral and central nociceptive neurons are specified early in development, and recent studies have identified key molecular pathways that control their genesis. Neurotrophins, normally noted for their role in sensory neuron survival, are now known to affect almost every aspect of peripheral nociceptor development well into postnatal life.

  • A combination of pathway tracing and synaptic and systems electrophysiology has provided a picture of the formation of early sensory circuits in the developing dorsal horn of the spinal cord, and their ability to process nociceptive and non-nociceptive information.

  • In many respects, newborn sensory circuits are more excitable than their mature counterparts and receptive fields gradually become tuned during the postnatal period. There is evidence to indicate that this tuning arises from the refinement of afferent excitatory inputs and the maturation of inhibitory processes, both locally and descending from the brainstem.

  • The activity-dependence of excitatory and inhibitory synaptic maturation in the dorsal horn has been a recent focus of research, along with increasing evidence for the ability of both non-noxious and noxious sensory activity to influence the development of pain processing. The mechanisms by which early tissue damage and inflammation might affect future pain processing are discussed in this review.

  • The study of developing nociceptive pathways can be translated into an increased understanding of paediatric pain. Such research should help us to design better strategies for the relief of pain in infants and children.

Abstract

The study of pain development has come into its own. Reaping the rewards of years of developmental and molecular biology, it has now become possible to translate fundamental knowledge of signalling pathways and synaptic physiology into a better understanding of infant pain. Research has cast new light on the physiological and pharmacological processes that shape the newborn pain response, which will help us to understand early pain behaviour and to design better treatments. Furthermore, it has shown how developing pain circuitry depends on non-noxious sensory activity in the healthy newborn, and how early injury can permanently alter pain processing.

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Figure 1: Neurotrophins and nociceptor development.
Figure 2: Reflex modules and nociceptive responses in neonates.
Figure 3: Schematic diagram of the synaptic changes that take place in the superficial laminae of the dorsal horn over the first 2–3 postnatal weeks.
Figure 4: Activity-dependent development in spinal cord sensory connections.

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Acknowledgements

The support of the Medical Research Council and the Wellcome Trust is gratefully acknowledged.

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DATABASES

Entrez

α2-AR

GDNF

Lbx1

Lmx1b

NGN1

Pax2

PN3

TrkA

TrkB

TrkC

TRPV1

FURTHER INFORMATION

The London Pain Consortium

WellChild Pain Research Centre

Glossary

TYROSINE KINASE RECEPTORS

(Trk). Neurotrophic factors — nerve growth factor (NGF), neurotrophin 3 (NT3), NT4/5 and brain-derived neurotrophic factor (BDNF) — act through a family of receptor proteins, the Trk receptors. TrkA is primarily the receptor for NGF, TrkB for BDNF and NT4/5, and TrkC for NT3.

C FIBRES

Small diameter unmyelinated primary afferent sensory fibres, with small cell bodies in the dorsal root ganglion. Most are nociceptors. They divide into a neuropeptide-containing, Trk receptor-expressing group and a lectin IB4-binding group, although the functional implications of this are still unclear.

A FIBRES

Large diameter myelinated primary afferent sensory fibres, with large cell bodies in the dorsal root ganglion. The largest diameter Aβ fibres are mainly low-threshold mechanoceptors, and the smaller Aδ fibres are both mechanoreceptors and nociceptors.

EMBRYONIC DAY

(E). These are dated from the time of fertilization. Rat gestation is 21.5 days, mouse a little shorter. Rats are born relatively early in terms of CNS development and the early postnatal period is often paralleled with the final gestation of development in humans.

RECEPTIVE FIELD

The area on the body surface that, when stimulated, evokes action potentials in a given neuron.

MONOSYNAPTIC

A direct synaptic input from pre- to postsynaptic neurons with no involvement of interneurons in between.

INTERSEGMENTAL REFLEXES

Motor reponses evoked by sensory stimulation in different spinal segments.

POSTCONCEPTIONAL WEEKS

Postconceptional age is the age of a premature human infant dated from the estimated time of conception.

EXCITATORY AND INHIBITORY POSTSYNAPTIC CURRENTS

(EPSCs and IPSCs). When a neuron is voltage clamped, ion flow across a membrane can be measured as electric current while the membrane potential is controlled with a feedback amplifier. Whole-cell patch clamping has extended the technique to allow recording of excitatory and inhibitory postsynaptic currents following synaptic activation of cells in a tissue slice or even in vivo.

PERIAQUEDUCTAL GREY

An area of the brainstem that surrounds the aqueduct connecting the third and fourth ventricles. This area projects to the medullary raphe region, which, in turn, sends projections down the dorsolateral funiculus of the spinal cord to the dorsal horn. This pathway is known to strongly modulate spinal pain processing.

RECEPTOR SUBUNITS

Ion channels are generally made up of several glycoprotein subunits that surround a central pore. These subunits can confer special characteristics on a channel, such as increased calcium permeability or longer opening times. The subunits of many channels change with development, thereby altering the channel properties.

HEBBIAN WEAKENING

Hebb proposed that if a neuron, A, took part in firing another neuron, B, then a plastic change would occur in the synapse between neurons A and B, such that the connection between A and B would be strengthened. This has been extended to include the opposite effect — that is, failure to take part in firing leads to synaptic weakening.

REVERSAL POTENTIAL

The membrane potential at which chemical and electrical drive are equal and opposite, so there is no net flow of ions across the membrane. The direction of flow reverses above and below this potential.

SPARED NERVE INJURY AND CHRONIC CONSTRICTION INJURY

(SNI and CCI). Animal models of neuropathic pain aim to produce a partial denervation and/or inflammation around a nerve, as this seems to trigger characteristic allodynia or touch-evoked pain. SNI involves ligation of two nerves that supply the lateral hind paw, while leaving one intact; CCI involves tying loose ligatures around a major hindlimb nerve.

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Fitzgerald, M. The development of nociceptive circuits. Nat Rev Neurosci 6, 507–520 (2005). https://doi.org/10.1038/nrn1701

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