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  • Review Article
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The molecular dynamics of pain control

Nature Reviews Neuroscience volume 2, pages 83–91 (2001)Cite this article

Key Points

  • Different chronic pain states generate different neurochemical changes in sensory fibres and the spinal cord. Understanding these distinct molecular signatures might be the key to effective pain control.

  • Sensory fibres carry information from the skin and most internal tissues to the spinal cord. Anatomically, there are two broad groups of sensory fibre: myelinated A fibres and smaller diameter, unmyelinated C fibres. Most C fibres are polymodal nociceptors that respond to all forms of noxious stimulation.

  • C fibres can be divided into two groups. One group expresses receptors for GDNF, and terminates almost exclusively within the deeper parts of the substantia gelatinosa of the spinal cord. The other group synthesizes peptides such as substance P, expresses the NGF receptor TrkA and terminates more superficially within the dorsal horn.

  • Noxious stimulation changes the phenotype of sensory neurons. In part, these changes are caused by a change in the levels of growth factors released from the injury area. NGF has been shown to regulate the behavioural sensitivity to pain. GDNF-sensitive sensory fibres might be involved in establishing chronic pain states.

  • Pain has sensory and affective qualities. The spinothalamic pathway, which originates primarily from neurons in the neck of the dorsal horn and terminates within the thalamus, is thought to convey the sensory qualities of the stimulus.

  • The spinoparabrachial pathway, which derives largely from lamina I neurons of the dorsal horn that express the substance P/neurokinin-1 (NK1) receptor, terminates within the parabrachial nuclei and periaqueductal grey. In turn, these areas project on areas such as the hypothalamus and amygdala that modulate the affective dimensions of pain and control autonomic activity.

  • Selective ablation of lamina I neurons that express the NK1 receptor revealed that this population is pivotal in the signalling of pain and the central maintenance of hyperalgesia.

  • Selective knockout of the NK1 receptor blunts the rewarding effect of morphine while leaving its analgesic effect largely intact. So NK1-receptor antagonists could counteract problems of morphine dependency in the clinic.

Abstract

Pain is necessary for survival, but persistent pain can result in anxiety, depression and a reduction in the quality of life. The discriminative and affective qualities of pain are both thought to be regulated in an activity-dependent fashion. Recent studies have identified cells and molecules that regulate pain sensitivity and the parallel pathways that distribute nociceptive information to limbic or sensory areas of the forebrain. Here, we emphasize the cellular and neurobiological consequences of pain, especially those that are involved in the generation and maintenance of chronic pain. These new insights into pain processing will significantly alter our approach to pain control and the development of new analgesics.

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Figure 1: C fibres and the dorsal horn of the spinal cord.
Figure 2: The main ascending and descending spinal pathways.
Figure 3: Lamina I neurons.
Figure 4: Internalization of the NK1 receptor in a neuron within the spinal cord.
Figure 5: Selective knockout of the NK1 receptor in mice.

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Acknowledgements

We would like to thank Dr Herve Bester for Figures 1 and 2 and for his comments on the manuscript. S.P.H would like to thank the Wellcome Trust and the BBSRC for support during the writing of this review. P.W.M would like to thank NINDS, NIDA and VA Merit Award for support for many of the studies referred to in the text.

Author information

Authors and Affiliations

  1. Department of Anatomy and Developmental Biology, Medawar Building, University College London, Gower Street, London, WC1E 6BT, UK

    Stephen P. Hunt

  2. Department of Preventive Sciences, Neuroscience and Psychiatry, University of Minnesota, 18–154 Moos Tower, 515 Delaware Street, Minneapolis, 55455, Minneapolis, USA

    Patrick W. Mantyh

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DATABASE LINKS

P2X3

GDNF

CGRP

NGF

TrkA

BNDF

NT-3

NK1 receptor

VR1

substance P

SNS

VRL-1

galanin

neuropeptide Y

Gap-43

GFAP

CCK-B receptor

Encyclopedia of Life Sciences links

Sodium channels

Somatosensory Systems

Substance P

Pain and analgesia

Glossary

BRAINSTEM

The brainstem extends from the spinal cord and rostrally includes the midbrain and thalamus. Surrounding the narrow ventricle of the midbrain is the periaqueductal grey, an area that is crucial for fight/flight behaviour and for the associated autonomic events.

SUBSTANTIA GELATINOSA

Lamina II of the spinal cord is also referred to (sometimes together with lamina I) as the substantia gelatinosa. This is the main site of termination of C-type sensory fibres, which are unmyelinated and so confer a gelatinous appearance on this region of the dorsal horn of the spinal cord when examined in unfixed preparations.

GLOMERULUS

Axon terminals end in a variety of configurations within the neuropil. The most common is en passant or de passage in which axons make simple synapses as they pass dendrites or cell bodies. By contrast, some axons end in — or produce strings of — enlargements that are often packed with synaptic vesicles. These glomerular-type endings synapse with large numbers of dendrites and other axons clustered around the glomerular ending.

SUBSTANCE P

Substance P is an 11-amino-acid tachykinin peptide neurotransmitter that binds preferentially to the NK1 receptor. A second tachykinin, NKA, also has high affinity for this receptor, suggesting that to refer to the NK1 receptor as 'the substance P receptor' could be misleading.

PERIPHERAL NERVE AXOTOMY

Surgical cutting or crushing of the peripheral nerve. The peripheral nerve can contain a mixture of sensory, autonomic or motor fibres depending on the particular nerve.

EXTRAVASATION

Refers to the leakage of plasma and plasma proteins from post-capillary venules — recognized as oedema.

HYPERALGESIA

Hyperalgesia refers to the perception of a stimulus as more painful than when previously experienced.

LAMINA I

The grey matter of the spinal cord has been divided up into ten laminae on the basis of the distribution of neuronal cell bodies and myelinated fibres. The most superficial is lamina I, which contains a mixture of neurons, ∼10% of which express the tachykinin NK1 receptor and project to higher centres of the brain.

CARRAGEENAN

Carrageenan is an inflammatory agent extracted from seaweed that induces localized swelling and pain that peaks three hours after injection. It is used to model inflammatory pain states observed in the clinic.

VON FREY THRESHOLDS

This is the point at which the stimulus — the Von Frey monofilament — produces a withdrawal response. The threshold is established by using filaments that exert a stimulus intensity that depends on their diameter.

DORSAL ROOT GANGLION

The cell bodies of sensory neurons are collected together in paired ganglia that lie alongside the spinal cord. These cell bodies are surrounded by satellite glial cells, which have much in common with the Schwann cells that ensheath peripheral axons. Very few synapses have been observed in these ganglia.

ALLODYNIA

Allodynia refers to the perception of a stimulus as painful when previously the stimulus was reported to be non-painful. As with hyperalgesia, this category was derived from observations on humans in which verbal reporting was used to assess pain sensitivity, and so it is very difficult to designate a change in pain sensitivity in animals as allodynic or hyperalgesic.

COMPLETE FREUNDS ADJUVANT

Complete Freunds Adjuvant is an inflammatory agent that induces localized swelling and pain that peaks three days after injection. It is used to model persistent pain states observed in the clinic.

CHUNG MODEL

There are several widely used neuropathic pain models. The Chung model is produced by a tight ligation of lumber dorsal roots L5 and L6 close to their exit from the dorsal root ganglion, leaving L4 intact. Stimuli applied within the peripheral cutaneous receptive field of L5 axons produce a heightened behavioural withdrawal response of the limb, suggesting increased sensitivity to previously non-noxious and noxious stimuli.

STRESS-INDUCED ANALGESIA

Stress has been shown to reduce sensitivity to noxious stimulation. In mice, moderate stress produces an analgesia that is mediated by endogenous opiates, whereas more severe stress results in a non-opioid-mediated, NK1-mediated and NMDA-receptor-mediated analgesia.

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Hunt, S., Mantyh, P. The molecular dynamics of pain control. Nat Rev Neurosci 2, 83–91 (2001). https://doi.org/10.1038/35053509

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