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Neuronal circuitry for pain processing in the dorsal horn

Key Points

  • The spinal dorsal horn is innervated by primary afferent fibres and contains a large number of excitatory (glutamatergic) and inhibitory (GABA (γ-aminobutyric acid)-ergic or glycinergic) interneurons, as well as projection neurons that convey sensory information to several brain areas. The interneurons regulate transmission of this information to projection cells and to local reflex pathways. There are also descending modulatory inputs from the brainstem.

  • The dorsal horn can be divided into six parallel laminae, each of which has a distinctive pattern of primary afferent input — for example, nociceptive primary afferents terminate mainly in lamina I and lamina II. Projection neurons are concentrated in lamina I and scattered through laminae III–VI. In all laminae, interneurons make up the great majority of the neuronal population.

  • Despite its importance in pain mechanisms, we still know little about the neuronal organisation and synaptic circuitry of the dorsal horn. This is largely because of the diversity of the neurons, which has made it difficult to recognize functional populations.

  • Recent studies have begun to reveal discrete classes of inhibitory and excitatory interneurons, as well as certain distinctive types of projection neuron. There have also been important advances in our understanding of the structure and function of primary afferents.

  • Based on these studies, we can now begin to map some of the neuronal circuits. For example, many projection neurons in lamina I and some of those in lamina III receive a powerful direct input from nociceptive primary afferents. There is also evidence that projection neurons are selectively innervated by particular types of interneuron.

  • Several changes that could contribute to chronic pain have been identified in the dorsal horn following inflammation or nerve injury. Proposed mechanisms include changes affecting inhibitory interneurons or their synapses, development of long-term potentiation and alterations in the excitability of neurons.

  • Future studies will need to investigate the synaptic organization of the dorsal horn, and the expression of receptors and ion channels on different neuronal populations. These should lead to the identification of new molecular targets for pain treatment, as well as allowing us to identify (and ideally prevent) changes in the dorsal horn that underlie chronic pain.

Abstract

Neurons in the spinal dorsal horn process sensory information, which is then transmitted to several brain regions, including those responsible for pain perception. The dorsal horn provides numerous potential targets for the development of novel analgesics and is thought to undergo changes that contribute to the exaggerated pain felt after nerve injury and inflammation. Despite its obvious importance, we still know little about the neuronal circuits that process sensory information, mainly because of the heterogeneity of the various neuronal components that make up these circuits. Recent studies have begun to shed light on the neuronal organization and circuitry of this complex region.

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Figure 1: Laminar organization of the dorsal horn and primary afferent inputs.
Figure 2: Classification of lamina II interneurons.
Figure 3: Projection neurons.
Figure 4: Neuronal circuits involving projection neurons.

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Acknowledgements

Support from the Wellcome Trust is gratefully acknowledged. I also thank T. Yasaka, D.I. Hughes and E. Polgár for helpful discussion and advice.

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Glossary

Nocifensive reflex

A protective reflex generated in response to a damaging (or potentially damaging) stimulus.

Allodynia

Pain following a normally non-painful tactile or thermal stimulus.

Neuropathic pain

Pain resulting from pathology of the nervous system. Most commonly this is caused by conditions affecting peripheral nerves.

Nociceptive information

Stimuli through which we perceive damage (or potential damage) caused to the body by excessive heat, cold or physical injury, for example.

Laminae of Rexed

A system of 10 layers, described by Rexed, to divide the grey matter in the spinal cord.

Synaptic glomerulus

A complex structure in which a central axonal bouton (of primary afferent origin) is in synaptic contact with several surrounding profiles, including dendrites and peripheral axons.

Nucleus raphe magnus

The main source of descending serotonergic axons that innervate the dorsal horn.

Locus coeruleus

The major source of noradrenergic axons to the spinal cord.

Volume transmission

A form of neurotransmission in which a neurotransmitter is released directly into the non-synaptic extracellular space to activate nearby receptors.

Rostral ventromedial medulla

A region of the brainstem that includes the nucleus raphe magnus and gives rise to many descending axons that innervate the dorsal horn.

Delayed firing pattern

A response to injected depolarizing current in which a neuron generates action potentials after a delay.

Gap firing pattern

A response to injected depolarizing current in which an initial action potential is followed by a long inter-spike interval and then regular firing.

Reluctant firing pattern

This term is used to describe neurons that are resistant to action potential firing during injection of depolarizing current.

Hyperalgesia

Exaggerated pain in response to a noxious stimulus.

Transient receptor potential A1

(Often abbreviated to TRPA1.) A non-selective cation channel that is activated by cold and by various chemical irritants (including mustard oil), and that is expressed by certain nociceptive primary afferents (a subset of those that express transient receptor potential V1).

Transient receptor potential vanilloid1

(Often abbreviated to TRPV1.) A non-selective cation channel that can be activated by various noxious stimuli (including heat and application of capsaicin) and that is expressed by many nociceptive primary afferents.

Long-term potentiation

(Often abbreviated to LTP.) A form of synaptic plasticity that results in a long-lasting increase in the strength of synaptic transmission.

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Todd, A. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci 11, 823–836 (2010). https://doi.org/10.1038/nrn2947

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