Ex vivo nonviral gene delivery of μ-opioid receptor to attenuate cancer-induced pain

Cancer patients in pain require high doses of opioids and quickly become opioid-tolerant. Previous studies have shown that chronic cancer pain as well as high-dose opioid use lead to mu-opioid receptor downregulation. In this study we explore downregulation of the mu-opioid receptor gene (OPRM1), as a mechanism for opioid tolerance in the setting of opioid use for cancer pain. We demonstrate in a cohort of 84 cancer patients that high-dose opioid use correlates with OPRM1 hypermethylation in peripheral leukocytes of these patients. We then reverse-translate our clinical findings by creating a mouse cancer pain model; we create opioid tolerance in the mouse cancer model to mimic opioid tolerance in the cancer patients. Using this model we determine the functional significance of OPRM1 methylation on cancer pain and opioid tolerance. We focus on 2 main cells within the cancer microenvironment: the cancer cell and the neuron. We show that targeted re-expression of mu-opioid receptor on cancer cells inhibits mechanical and thermal hypersensitivity, and prevents opioid tolerance, in the mouse model. The resultant analgesia and protection against opioid tolerance are likely due to preservation of mu-opioid receptor expression on the cancer-associated neurons.

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“…Our results from this study and previous studies 31,33,36 highlight the role of peripheral opioid receptors in mediating cancer pain.…”

Section: Discussionsupporting

confidence: 81%

OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients

Viet

Dang

Aouizerat

et al. 2017

The Journal of Pain

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“…Oral carcinoma is comprised of malignant oral keratinocytes, which might serve as a potential source of opioids within the cancer microenvironment. Viral- and nonviral-mediated delivery of genes for the μ-opioid receptor and the endothelin B receptor ( OPRM1 and EDNRB , respectively) produce endogenous analgesia through the secretion of opioids by the carcinoma in preclinical oral cancer pain models (Viet et al, 2011 ; Yamano et al, 2017 ). Adenoviral transduction produces immune effects that prohibit clinical use (Nayak and Herzog, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Neutrophil-Mediated Endogenous Analgesia Contributes to Sex Differences in Oral Cancer Pain

Scheff

Bhattacharya

Dowse

et al. 2018

Front. Integr. Neurosci.

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The incidence of oral cancer in the United States is increasing, especially in young people and women. Patients with oral cancer report severe functional pain. Using a patient cohort accrued through the New York University Oral Cancer Center and immune-competent mouse models, we identify a sex difference in the prevalence and severity of oral cancer pain. A neutrophil-mediated endogenous analgesic mechanism is present in male mice with oral cancer. Local naloxone treatment potentiates cancer mediator-induced orofacial nociceptive behavior in male mice only. Tongues from male mice with oral cancer have significantly more infiltrating neutrophils compared to female mice with oral cancer. Neutrophils isolated from the cancer-induced inflammatory microenvironment express beta-endorphin and met-enkephalin. Furthermore, neutrophil depletion results in nociceptive behavior in male mice. These data suggest a role for sex-specific, immune cell-mediated endogenous analgesia in the treatment of oral cancer pain.

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“…S4) and performed a mouse paw withdrawal assay. Intraplantar injection of HSC-3 oral tongue cancer cell line conditioned media is routinely used as a model to study oral cancer pain 32,33 . The cell line supernatant induces mechanical allodynia and thermal hyperalgesia as demonstrated here in Fig.…”

Section: Depletion Of Oral Cancer Cell Line Evs Reduces Nociceptive Bmentioning

confidence: 99%

Oncogenes overexpressed in metastatic oral cancers from patients with pain: potential pain mediators released in exosomes

Bhattacharya

Veeramachaneni

Dolgalev

et al. 2020

Sci Rep

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Oral cancer patients experience pain at the site of the primary cancer. Patients with metastatic oral cancers report greater pain. Lack of pain identifies patients at low risk of metastasis with sensitivity = 0.94 and negative predictive value = 0.89. In the same cohort, sensitivity and negative predictive value of depth of invasion, currently the best predictor, were 0.95 and 0.92, respectively. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. We hypothesized that pain mediators would be overexpressed in metastatic cancers from patients reporting high pain. We identified 40 genes overexpressed in metastatic cancers from patients reporting high pain (n = 5) compared to N0 cancers (n = 10) and normal tissue (n = 5). The genes are enriched for functions in extracellular matrix organization and angiogenesis. They have oncogenic and neuronal functions and are reported in exosomes. Hierarchical clustering according to expression of neurotrophic and axon guidance genes also separated cancers according to pain and nodal status. Depletion of exosomes from cancer cell line supernatant reduced nociceptive behavior in a paw withdrawal assay, supporting a role for exosomes in cancer pain. The identified genes and exosomes are potential therapeutic targets for stopping cancer and attenuating pain.

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Ex vivo nonviral gene delivery of μ-opioid receptor to attenuate cancer-induced pain

Cited by 19 publications

References 59 publications

OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients

OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients

Neutrophil-Mediated Endogenous Analgesia Contributes to Sex Differences in Oral Cancer Pain

Oncogenes overexpressed in metastatic oral cancers from patients with pain: potential pain mediators released in exosomes

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