The Neurobiology of Cancer Pain

Schmidt, Brian L.

doi:10.1177/1073858414525828

Cited by 82 publications

(63 citation statements)

References 124 publications

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“…Thus, while skin hyperalgesia as assessed by quantitative sensory testing may be common in humans with moderate to severe skeletal pain, these patients rarely self-report skin hypersensitivity as their attention maybe focused on obtaining relief from the underlying skeletal pain. Indeed, it has been noted by clinicians that cancer patients rarely report skin pain even when they are reporting severe cancer pain [56]. …”

Section: Discussionmentioning

confidence: 99%

“…Recently, hypersensitivity of the skin has been detected in human patients and preclinical animal models of osteoarthritis, low back pain, and bone cancer pain [4; 33; 43; 56; 58; 59; 72]. Given that skin hypersensitivity can be measured much more quickly and easily than skeletal pain-related behaviors, a major question is whether skeletal pain-induced hypersensitivity of the skin is an appropriate and reliable surrogate for assessing skeletal pain.…”

Section: Introductionmentioning

confidence: 99%

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Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain

Guedon

Longo

Majuta

et al. 2016

Pain

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Recent studies have suggested that in humans and animals with significant skeletal pain, changes in the mechanical hypersensitivity of the skin can be detected. However, whether measuring changes in skin hypersensitivity can be a reliable surrogate for measuring skeletal pain itself remains unclear. To explore this question we generated skeletal pain by injecting and confining GFP-transfected NCTC 2472 osteosarcoma cells unilaterally to the femur of C3H male mice. Beginning at day 7 post-tumor injection, animals were administered vehicle, an antibody to the P2X3 receptor (anti-P2X3) or anti-NGF antibody. Pain and analgesic efficacy was then measured on days 21, 28 and 35 post-tumor injection using a battery of skeletal pain-related behaviors and von Frey assessment of mechanical hypersensitivity on the plantar surface of the hindpaw. Animals with bone cancer pain treated with anti-P2X3 showed a reduction in skin hypersensitivity but no attenuation of skeletal pain behaviors. Whereas animals with bone cancer pain treated with anti-NGF showed a reduction in both skin hypersensitivity and skeletal pain behaviors. These results suggest that while bone cancer can induce significant skeletal pain-related behaviors and hypersensitivity of the skin, relief of hypersensitivity of the skin is not always accompanied by attenuation of skeletal pain. Understanding the relationship between skeletal and skin pain may provide insight into how pain is processed and integrated and help define the preclinical measures of skeletal pain that are predictive endpoints for clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain

Guedon

Longo

Majuta

et al. 2016

Pain

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“…Investigation of the basic elements of the intercellular pathways has yielded a better understanding of this process [18]. It is generally accepted that cancers secrete algogenic mediators that subsequently sensitize or activate neurons in the cancer microenvironment.…”

Section: Pain Reveals Essential Steps In Carcinogenesismentioning

confidence: 99%

“…It is generally accepted that cancers secrete algogenic mediators that subsequently sensitize or activate neurons in the cancer microenvironment. These algogens include proteases, endothelin-1 (ET-1), ATP, protons, neurotrophic factors, bradykinin and tumor necrosis factor [18]. Secreted products from cancer alone activate primary afferent neurons.…”

Section: Pain Reveals Essential Steps In Carcinogenesismentioning

confidence: 99%

What pain tells us about cancer

Schmidt

2015

Pain

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Cancer pain sends a message. It is frightening to the patient. It heralds progression or recurrence to the oncologist. It is a biologic readout of the cancer-nerve interaction for the scientist. Nerves have been considered bystanders within the cancer microenvironment. However, emerging information suggests that nerves are recruited and participate in the carcinogenic process. These newly formed fibers respond to mediators secreted by constituents of the cancer microenvironment. In this manner these nerves serve as bellwethers and sensors embedded within the cancer. When we rigorously assess patients’ cancer pain we gain insight into the action of cancer. An enhanced understanding of cancer pain offers biologic questions which if answered might not only provide relief from cancer pain but might also improve survival.

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“…While the etiology of cancer pain remains unknown, an often-cited hypothesis for cancer pain is that cancer cells and leukocytes within the cancer microenvironment produce mediators that sensitize and activate nociceptors [58]. Despite the strong inflammatory response that characterizes oral cancers, the role of leukocyte infiltration and associated secretion of mediators in oral cancer pain is unknown.…”

Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor alpha secreted from oral squamous cell carcinoma contributes to cancer pain and associated inflammation

Scheff

Bhattacharya

et al. 2017

Pain

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Patients with oral cancer report severe pain during function. Inflammation plays a role in the oral cancer microenvironment; however, the role of immune cells and associated secretion of inflammatory mediators in oral cancer pain has not been well defined. In this study, we used 2 oral cancer mouse models: a cell line supernatant injection model and the 4-nitroquinoline-1-oxide (4NQO) chemical carcinogenesis model. We used the 2 models to study changes in immune cell infiltrate and orofacial nociception associated with oral squamous cell carcinoma (oSCC). Oral cancer cell line supernatant inoculation and 4NQO-induced oSCC resulted in functional allodynia and neuronal sensitization of trigeminal tongue afferent neurons. Although the infiltration of immune cells is a prominent component of both oral cancer models, our use of immune-deficient mice demonstrated that oral cancer–induced nociception was not dependent on the inflammatory component. Furthermore, the inflammatory cytokine, tumor necrosis factor alpha (TNFα), was identified in high concentration in oral cancer cell line supernatant and in the tongue tissue of 4NQO-treated mice with oSCC. Inhibition of TNFα signaling abolished oral cancer cell line supernatant-evoked functional allodynia and disrupted T-cell infiltration. With these data, we identified TNFα as a prominent mediator in oral cancer–induced nociception and inflammation, highlighting the need for further investigation in neural–immune communication in cancer pain.

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The Neurobiology of Cancer Pain

Cited by 82 publications

References 124 publications

Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain

Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain

What pain tells us about cancer

Tumor necrosis factor alpha secreted from oral squamous cell carcinoma contributes to cancer pain and associated inflammation

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