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Cited by 1,774Pain Mechanisms and TreatmentsPain Management and TreatmentIon Channels and Receptors

The induction of pain: an integrative review

Millan, Mark J.·1999·Progress in Neurobiology
DOI 10.1016/s0301-0082(98)00048-3
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Abstract

The highly disagreeable sensation of pain results from an extraordinarily complex and interactive series of mechanisms integrated at all levels of the neuroaxis, from the periphery, via the dorsal horn to higher cerebral structures. Pain is usually elicited by the activation of specific nociceptors ('nociceptive pain'). However, it may also result from injury to sensory fibres, or from damage to the CNS itself ('neuropathic pain'). Although acute and subchronic, nociceptive pain fulfils a warning role, chronic and/or severe nociceptive and neuropathic pain is maladaptive. Recent years have seen a progressive unravelling of the neuroanatomical circuits and cellular mechanisms underlying the induction of pain. In addition to familiar inflammatory mediators, such as prostaglandins and bradykinin, potentially-important, pronociceptive roles have been proposed for a variety of 'exotic' species, including protons, ATP, cytokines, neurotrophins (growth factors) and nitric oxide. Further, both in the periphery and in the CNS, non-neuronal glial and immunecompetent cells have been shown to play a modulatory role in the response to inflammation and injury, and in processes modifying nociception. In the dorsal horn of the spinal cord, wherein the primary processing of nociceptive information occurs, N-methyl-D-aspartate receptors are activated by glutamate released from nocisponsive afferent fibres. Their activation plays a key role in the induction of neuronal sensitization, a process underlying prolonged painful states. In addition, upon peripheral nerve injury, a reduction of inhibitory interneurone tone in the dorsal horn exacerbates sensitized states and further enhance nociception. As concerns the transfer of nociceptive information to the brain, several pathways other than the classical spinothalamic tract are of importance: for example, the postsynaptic dorsal column pathway. In discussing the roles of supraspinal structures in pain sensation, differences between its 'discriminative-sensory' and 'affective-cognitive' dimensions should be emphasized. The purpose of the present article is to provide a global account of mechanisms involved in the induction of pain. Particular attention is focused on cellular aspects and on the consequences of peripheral nerve injury. In the first part of the review, neuronal pathways for the transmission of nociceptive information from peripheral nerve terminals to the dorsal horn, and therefrom to higher centres, are outlined. This neuronal framework is then exploited for a consideration of peripheral, spinal and supraspinal mechanisms involved in the induction of pain by stimulation of peripheral nociceptors, by peripheral nerve injury and by damage to the CNS itself. Finally, a hypothesis is forwarded that neurotrophins may play an important role in central, adaptive mechanisms modulating nociception. An improved understanding of the origins of pain should facilitate the development of novel strategies for its more effective treatment.

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Crossref · 10.1016/s0301-0082(98)00048-3

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1977 of 1977 references verified0 citation errors · 0 not checkable

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  • The periaqueductal gray receives monosynaptic inputs from nociceptive spinal projection neurons and top-down projections from ventromedial prefrontal cortex, positioning it as a potential comparator of bottom-up aversive sensations with expectations.

    “The PAG receives monosynaptic inputs from both nociceptive spinal projection neurons28 and top-down projections from the vmPFC30, positioning it as a potential comparator of ‘bottom up’ aversive sensations with expectations.”

    From Representation of aversive prediction errors in the human periaqueductal gray (2014) · cites this paper as [28]

  • In the final dynamic causal model, noxious input had direct effects on periaqueductal gray and modulatory effects on ascending putamen-to-orbitofrontal, putamen-to-anterior-mid-cingulate, and midbrain-to-anterior-mid-cingulate connections.

    “Noxious input had direct effects on PAG, in keeping with the known anatomy of the ascending spinomesencephalic nociceptive pathway28, and modulatory effects on ascending putamen-to-OFC, putamen-to-aMCC, and midbrain-to-aMCC connections.”

    From Representation of aversive prediction errors in the human periaqueductal gray (2014) · cites this paper as [28]

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Authors
Millan, M. J.
Affiliations
Institut de Recherches Internationales Servier (France) (FR)
Corresponding author
Millan, Mark J.
ORCID
Millan, Mark J.
Venue
Progress in Neurobiology
Publisher
Elsevier BV
Published
1999-01
Volume
57
Issue
1
Pages
1-164
ISSN
0301-0082 (ISSN-L)
DOI
10.1016/s0301-0082(98)00048-3
OpenAlex
W2123258170
Cited by
1,774
References
1,977
Citations by year
2026: 6 · 2025: 24 · 2024: 22 · 2023: 30 · 2022: 53 · 2021: 40 · 2020: 42 · 2019: 49 · 2018: 61 · 2017: 68 · 2016: 72 · 2015: 66 · 2014: 76 · 2013: 74 · 2012: 93
FWCI
8.64
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Progress in Neurobiology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
pain induction, nociception, nociceptors, neuropathic pain, dorsal horn, NMDA receptor, neuronal sensitization, peripheral nerve injury, ATP, cytokines, nitric oxide, neurotrophins, glial modulation, dorsal column pathway, spinothalamic tract, affective pain
MeSH terms
Animals, Brain, Humans, Synaptic Transmission, Nociceptors, Pain, Spinal Cord

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