Key Points
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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.
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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.
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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.
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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.
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Tumour growth entraps and injures nerves, causing neuropathic pain.
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The spinal cord and forebrain undergo neurochemical and structural changes as a state of chronic pain develops.
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Cancer pain frequently becomes more severe as the disease progresses, and might require different types of analgesic at different time points.
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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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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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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
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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
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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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DOI: https://doi.org/10.1038/nrc747
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