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Molecular mechanisms of cancer pain

Nature Reviews Cancer volume 2, pages 201–209 (2002)Cite this article

Key Points

  • As advances in cancer detection and therapy are extending the life expectancy of cancer patients, there is increasing focus on improving the quality of life of patients. New approaches are desperately needed to control cancer-associated pain.

  • Sensory information from peripheral tissues is transmitted to the spinal cord and brain by primary afferent sensory neurons. Specialized sensory neurons — known as nociceptors — detect and convert environmental stimuli that are perceived as harmful into electrochemical signals that are transmitted to the central nervous system.

  • Tumours secrete a variety of factors that sensitize or directly excite primary afferent neurons, causing the sensation of pain. Receptors for many of these factors are expressed by primary afferent neurons.

  • Both the intracellular and extracellular pH of solid tumours are lower than that of surrounding normal tissues, which can also activate sensory neurons and cause pain in cancer patients.

  • Tumour growth entraps and injures nerves, causing neuropathic pain.

  • The spinal cord and forebrain undergo neurochemical and structural changes as a state of chronic pain develops.

  • Cancer pain frequently becomes more severe as the disease progresses, and might require different types of analgesic at different time points.

  • For the first time, animal models of cancer pain are now available. These will offer insight into one of the main conundrums of cancer pain — why the severity of this pain is so variable from patient to patient, tumour to tumour, and even from site to site.

Abstract

Pain is the most disruptive influence on the quality of life of cancer patients. Although significant advances are being made in cancer treatment and diagnosis, the basic neurobiology of cancer pain is poorly understood. New insights into these mechanisms are now arising from animal models, and have the potential to fundamentally change the way that cancer pain is controlled.

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Figure 1: Detection by sensory neurons of noxious stimuli produced by tumours.
Figure 2: The tumour–nociceptor interface.
Figure 3: Cancer induced reorganization of the central nervous system.

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Acknowledgements

We would like to thank M. Sabino and D. Mach for their invaluable comments and suggestions, and the National Institute of Neurological Disorders and Stroke, the National Institute of Drug Abuse, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Veterans Administration for their support of research into the mechanisms that generate cancer pain.

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Authors and Affiliations

  1. Departments of Preventive Sciences, Psychiatry and Neuroscience, University of Minnesota, 18-208 Moos Tower, 515 Delaware Street SE, Minneapolis, 55455, Minnesota, USA

    Patrick W. Mantyh

  2. Department of Orthopaedic Surgery, Medical School and Cancer Center, University of Minnesota, 420 Delaware Street SE, Minneapolis, 55455, Minnesota, USA

    Denis R. Clohisy

  3. Institute of Child Health and Institute of Neurology, University College London and National Hospital for Neurology and Neurosurgery, 30 Guilford Street, London, WC1N 1EH, UK

    Martin Koltzenburg

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

    Steve P. Hunt

Authors
  1. Patrick W. Mantyh
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  2. Denis R. Clohisy
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  3. Martin Koltzenburg
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Correspondence to Patrick W. Mantyh.

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DATABASES

CancerNet:

bone cancer

prostate cancer

 LocusLink:

ASIC3

COX1

COX2

endothelin-1

endothelin-2

endothelin-3

epidermal growth factor

c-Fos

interleukin-1

interleukin-6

nerve growth factor

neurokinin-1 receptor

OPG

OPGL

P2X3

platelet-derived growth factor

RANK

TNFR

TNF-α

transforming growth factor-β

tubulin

VR1

 Medscape DrugInfo:

aspirin

gabapentin

ibuprofen

paclitaxel

vincristine

FURTHER INFORMATION

American Alliance of Cancer Pain Initiatives

American Cancer Society

American Pain Foundation

American Pain Society

Evidence-Based Health Care, Oxford

International Association for the Study of Pain (IASP)

National Cancer Institute

National Institute of Drug Abuse

National Institute of Neurological Disorders and Stroke

Neurosystems Laboratory

NIH Clinical Trials Listing

Society for Neuroscience

University of Minnesota Cancer Center

Glossary

PRIMARY AFFERENT SENSORY NEURON

A neuron that has a cell body located in the dorsal root ganglion and has one axon that innervates peripheral tissue and one axon that projects to the spinal cord or the brainstem. Humans have 2–3 million primary afferent sensory neurons, which innervate almost every organ of the body.

TRIGEMINAL GANGLIA

The ganglia that house the cell bodies of primary afferent neurons that innervate the head and neck.

DORSAL ROOT GANGLION

The cell bodies of sensory neurons are collected together in paired ganglia that lie alongside the dorsal spinal cord. These sensory-neuron cell bodies are surrounded by satellite glial cells.

NOCICEPTOR

A primary afferent sensory neuron that is activated by tissue-damage-related stimuli.

PURINERGIC RECEPTORS

A family of cell-surface receptors that are activated by ATP and other nucleotides that mediate a broad spectrum of physiological responses, including activation of nociceptors.

ENDOTHELINS

A family of three peptides that are released from endothelial cells and some tumour cells. These peptides can activate nociceptors, mount an inflammatory response, and stimulate angiogenesis and growth of tumour cells.

PROSTAGLANDINS

Pro-inflammatory lipids that are formed from arachidonic acid by the action of cyclooxygenase enzymes and other downstream synthetases.

BRADYKININ

A peptide that, when applied to primary afferent sensory nerve terminals, produces pain and sensitization of the sensory neuron to other noxious and non-noxious stimuli.

PERIPHERAL SENSITIZATION

An altered state of nociceptor function that is characterized by a lowered threshold of activation and an increased response to suprathreshold stimuli.

HYPERALGESIA

An increased response to a stimulus that is normally painful.

ALLODYNIA

Pain caused by a stimulus that does not normally provoke pain.

ASTROCYTES

The most numerous type of glial cell in the central nervous system. Astrocytes regulate the extracellular neuronal environment.

CENTRAL SENSITIZATION

An increased responsiveness of pain transmission to neurons in the spinal cord — usually caused by neurochemical changes in the spinal cord, brainstem or forebrain.

SPINOTHALAMIC TRACT NEURONS

A small group of neurons that are located in the dorsal horn of the spinal cord and are involved in the ascending conduction of pain and temperature.

AMYGDALA

An area of the forebrain that is involved in the formation of emotional memories, and the generation of fear, anxiety and stress that occurs in response to noxious stimuli.

PERIOSTEUM

The thin, highly innervated, fibrous tissue sheath that covers the outside of mineralized bone.

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Mantyh, P., Clohisy, D., Koltzenburg, M. et al. Molecular mechanisms of cancer pain. Nat Rev Cancer 2, 201–209 (2002). https://doi.org/10.1038/nrc747

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