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

Scheff, Nicole N.; Bhattacharya, Aditi; Dowse, Edward; Dang, Richard X.; Dolan, John C.; Wang, Susanna; Kim, Hyesung; Albertson, Donna G.; Schmidt, Brian L.

doi:10.3389/fnint.2018.00052

Cited by 36 publications

(63 citation statements)

References 63 publications

(85 reference statements)

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“…Leukocytes (neutrophils, monocytes/macrophages, and lymphocytes) are a rich source of endogenous opioid peptides [ [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] ] that inhibit nociceptive transmission by binding to peripheral opioid receptors [ [14] , [15] , [16] ]. During inflammation, leukocytes are recruited to the site of damage [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Heme attenuates beta-endorphin levels in leukocytes of HIV positive individuals with chronic widespread pain

et al. 2020

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The prevalence of chronic widespread pain (CWP) in people with HIV is high, yet the underlying mechanisms are elusive. Leukocytes synthesize the endogenous opioid, β-endorphin, within their endoplasmic reticulum (ER). When released into plasma, β-endorphin dampens nociception by binding to opioid receptors on sensory neurons. We hypothesized that the heme-dependent redox signaling induces ER stress, which attenuates leukocyte β-endorphins levels/release, thereby increasing pain sensitivity in people with HIV. Results demonstrated that HIV positive individuals with CWP had increased plasma methemoglobin, erythrocytes membrane oxidation, hemolysis, and low plasma heme scavenging enzyme, hemopexin, compared to people with HIV without CWP and HIV-negative individuals with or without pain. In addition, the leukocytes from people with HIV with CWP had attenuated levels of the heme metabolizing enzyme, heme oxygenase-1, which metabolizes free heme to carbon-monoxide and biliverdin. These individuals also had elevated ER stress, and low β-endorphin in leukocytes. In vitro, heme exposure or heme oxygenase-1 deletion, decreased β-endorphins in murine monocytes/macrophages. Treating cells with a carbon-monoxide donor or an ER stress inhibitor, increased β-endorphins. To mimic hemolytic effects in a preclinical model, C57BL/6 mice were injected with phenylhydrazine hydrochloride (PHZ). PHZ increased cell-free heme and ER stress, decreased leukocyte β-endorphin levels and hindpaw mechanical sensitivity thresholds. Treatment of PHZ-injected mice with hemopexin blocked these effects, suggesting that heme-induced ER stress and a subsequent decrease in leukocyte β-endorphin is responsible for hypersensitivity in people with HIV.

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Section: Introductionmentioning

confidence: 99%

Heme attenuates beta-endorphin levels in leukocytes of HIV positive individuals with chronic widespread pain

et al. 2020

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“…Oral cancer patients report severe function-induced pain; patients experience impaired speech, swallowing, eating, and drinking (Bjordal et al, 2001) and severity is greater in females. We previously demonstrated a sex difference in the prevalence and severity of oral squamous cell carcinoma (SCC)-induced nociception (Scheff et al, 2018). Female mice with 4-nitroquinoline-1-oxide (4NQO)-induced oral SCC exhibited more orofacial nociceptive behavior compared to male mice (Scheff et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…We previously demonstrated a sex difference in the prevalence and severity of oral squamous cell carcinoma (SCC)-induced nociception (Scheff et al, 2018). Female mice with 4-nitroquinoline-1-oxide (4NQO)-induced oral SCC exhibited more orofacial nociceptive behavior compared to male mice (Scheff et al, 2018). Furthermore, infiltrating neutrophils contribute to decreased nociceptive behavior in male mice during early 4NQO-induced carcinogenesis through opioid-mediated endogenous anti-nociception (Scheff et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Female mice with 4-nitroquinoline-1-oxide (4NQO)-induced oral SCC exhibited more orofacial nociceptive behavior compared to male mice (Scheff et al, 2018). Furthermore, infiltrating neutrophils contribute to decreased nociceptive behavior in male mice during early 4NQO-induced carcinogenesis through opioid-mediated endogenous anti-nociception (Scheff et al, 2018). Activation of opioid receptors on peripheral sensory nerves can produce anti-nociception (Stein et al, 1991, 2003; Mousa et al, 2007; Hua and Cabot, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Granulocyte-Colony Stimulating Factor-Induced Neutrophil Recruitment Provides Opioid-Mediated Endogenous Anti-nociception in Female Mice With Oral Squamous Cell Carcinoma

Scheff

Alemu

Klares

et al. 2019

Front. Mol. Neurosci.

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Oral cancer patients report severe function-induced pain; severity is greater in females. We hypothesize that a neutrophil-mediated endogenous analgesic mechanism is responsible for sex differences in nociception secondary to oral squamous cell carcinoma (SCC). Neutrophils isolated from the cancer-induced inflammatory microenvironment contain β-endorphin protein and are identified by the Ly6G+ immune marker. We previously demonstrated that male mice with carcinogen-induced oral SCC exhibit less nociceptive behavior and a higher concentration of neutrophils in the cancer microenvironment compared to female mice with oral SCC. Oral cancer cells secrete granulocyte colony stimulating factor (G-CSF), a growth factor that recruits neutrophils from bone marrow to the cancer microenvironment. We found that recombinant G-CSF (rG-CSF, 5 μg/mouse, intraperitoneal) significantly increased circulating Ly6G+ neutrophils in the blood of male and female mice within 24 h of administration. In an oral cancer supernatant mouse model, rG-CSF treatment increased cancer-recruited Ly6G+ neutrophil infiltration and abolished orofacial nociceptive behavior evoked in response to oral cancer supernatant in both male and female mice. Local naloxone treatment restored the cancer mediator-induced nociceptive behavior. We infer that rG-CSF-induced Ly6G+ neutrophils drive an endogenous analgesic mechanism. We then evaluated the efficacy of chronic rG-CSF administration to attenuate oral cancer-induced nociception using a tongue xenograft cancer model with the HSC-3 human oral cancer cell line. Saline-treated male mice with HSC-3 tumors exhibited less oral cancer-induced nociceptive behavior and had more β-endorphin protein in the cancer microenvironment than saline-treated female mice with HSC-3 tumors. Chronic rG-CSF treatment (2.5 μg/mouse, every 72 h) increased the HSC-3 recruited Ly6G+ neutrophils, increased β-endorphin protein content in the tongue and attenuated nociceptive behavior in female mice with HSC-3 tumors. From these data, we conclude that neutrophil-mediated endogenous opioids warrant further investigation as a potential strategy for oral cancer pain treatment.

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“…Leukocytes (neutrophils, monocytes/macrophages, and lymphocytes) are a rich source of endogenous opioid peptides (5)(6)(7)(8)(9)(10)(11)(12)(13) that inhibit nociceptive transmission by binding to peripheral opioid receptors (14)(15)(16). During inflammation, leukocytes are recruited to the site of damage (17).…”

Section: Introductionmentioning

confidence: 99%

Heme Attenuates Endogenous Opioid Levels in Leukocytes of HIV positive individuals with Chronic Widespread Pain

Aggarwal

DeBerry

Ahmad

et al. 2020

Preprint

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The prevalence of chronic widespread pain (CWP) in people with HIV (PWH) is high, yet the underlying mechanisms are elusive. Leukocytes synthesize the endogenous opioid, β-endorphin (β-END), within their endoplasmic reticulum (ER). When released into plasma, β-END dampens nociceptive transmission by binding to opioid receptors on sensory neurons. In the present study, we hypothesized that heme-induced ER stress attenuates leukocyte levels/release of β-END, thereby increasing pain sensitivity in PWH. Results demonstrate that PWH with CWP have fragile erythrocytes, high plasma levels of cell-free heme, and impaired heme metabolism. Leukocytes from PWH with CWP also had high ER stress and low β-END compared to PWH without CWP and HIV-negative individuals with or without pain. In vitro heme exposure decreased β-END levels/secretion in murine monocytes/macrophages, which was prevented by treatment with sodium 4phenylbutyrate, an ER stress inhibitor. To mimic hemolytic effects in a preclinical model in vivo, C57BL/6 mice were injected with phenylhydrazine hydrochloride (PHZ). PHZ increased cell-free heme and ER stress, decreased leukocyte β-END levels and hindpaw mechanical sensitivity thresholds. Treatment of PHZ-injected mice with the heme scavenger, hemopexin, blocked these effects, suggesting that heme-induced ER stress and a subsequent decrease in leukocyte β-END may contribute to CWP in PWH.

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

Cited by 36 publications

References 63 publications

Heme attenuates beta-endorphin levels in leukocytes of HIV positive individuals with chronic widespread pain

Heme attenuates beta-endorphin levels in leukocytes of HIV positive individuals with chronic widespread pain

Granulocyte-Colony Stimulating Factor-Induced Neutrophil Recruitment Provides Opioid-Mediated Endogenous Anti-nociception in Female Mice With Oral Squamous Cell Carcinoma

Heme Attenuates Endogenous Opioid Levels in Leukocytes of HIV positive individuals with Chronic Widespread Pain

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