Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (17 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2010)

Rodent pain models play an important role in understanding the mechanisms of nociception and have accelerated the search for new treatment approaches for pain. Creating an objective metric for orofacial nociception in these models presents significant technical obstacles. No animal assay accurately measures pain-induced orofacial dysfunction that is directly comparable to human orofacial dysfunction. We developed and validated a high throughput, objective, operant, nociceptive animal assay, and an instrument to perform the assay termed the dolognawmeter, for evaluation of conditions known to elicit orofacial pain in humans. Using the device our assay quantifies gnawing function in the mouse. We quantified a behavioral index of nociception and demonstrated blockade of nociception in three models of orofacial pain: (1) TMJ inflammation, (2) masticatory myositis, and (3) head and neck cancer. This assay will be useful in the study of nociceptive mediators involved in the development and progression of orofacial pain conditions and it will also provide a unique tool for development and assessment of new therapeutic approaches.

    Cover page: The dolognawmeter: A novel instrument and assay to quantify nociception in rodent models of orofacial pain
    • Thesis
    • Peer Reviewed
    UC San Francisco Electronic Theses and Dissertations (2011)

    Cancer pain creates a poor quality of life for cancer patients. Chronic

    cancer pain is a major public health problem in which little progress has been made in treatment. In this dissertation we propose that pain is the result of imbalance between algesic and analgesic mediators within the cancer microenvironment. Furthermore, this imbalance arises from downregulation by hypermethylation of genes coding for analgesic mediators, and re-expression of these mediators by demethylating drugs produces analgesia. We determine whether EDNRB and OPRM1, genes of receptors mediating analgesia, are hypermethylated in the tumors of oral cancer patients, compared to normal and oral dysplasia controls. To determine whether the expression of these genes mediates analgesia, we create an orthotopic oral cancer mouse model, where we re-express the EDNRB or OPRM1 gene using adenoviruses. Re-expression of EDNRB results in mechanical analgesia, and re-expression of OPRM1 results in mechanical and thermal analgesia in the mouse cancer pain model. Finally, we determine the analgesic potential of demethylating drugs decitabine and zebularine in the mouse cancer model. We show that combination therapy with these two drugs results in an antiproliferative and analgesic effect in the mouse model.

      Cover page: Epigenetic Silencing is a Novel Mechanism Controlling Cancer-Induced Pain
      • Thesis
      • Peer Reviewed
      UC San Francisco Electronic Theses and Dissertations (2010)

      Cancer pain is a frequent and disabling consequence for many patients yet the mechanism of cancer pain remains unknown largely due to its complex etiology. The objective of this thesis work was to investigate the potential of a peptide produced by carcinoma cells, endothelin, as a novel target for cancer pain management. This study provided evidence in support of Hypothesis 1: Oral squamous carcinoma cells produce endogenous opioids in response to changes in endothelin-1 signaling. Effects of endothelin-1 (ET-1) signaling on secretion of opioids by oral squamous cell carcinoma (SCC) were studied in vitro. Oral SCC cell line HSC-3 produces abundant ET-1 that can act in both an autocrine or paracrine manner. In the untreated oral SCC cells, endogenous opioids were detected in both cultured media and cell lysates. When treated with Endothelin-A receptor antagonist, secreted levels of &beta-endorphin and leu-enkephalin were increased; whereas treatment with Endothelin-B receptor agonist increased production of only &beta-endorphin. This apparent regulation of endogenous opioid levels by endothelin receptor drugs in vitro procured evidence suggesting that Hypothesis 2: Endothelin-A receptor antagonist and Endothelin-B receptor agonist attenuate carcinoma-induced nociception in cancer animals through regulation of endogenous opioids. Endothelin-A (ET-AR) antagonism has been demonstrated previously to attenuate carcinoma-mediated hyperalgesia in an orthotopic cancer pain mouse model. In this study, effects of ET-BR agonist in vivo were evaluated and determined to also result in significant increase in paw withdrawal thresholds, indicating attenuation of cancer-induced nociception. When peripheral &mu- or &delta-opioid receptor antagonists were administered following ET-AR antagonism, nociceptive attenuation was completely reversed. Attenuation from ET-BR agonism was likewise reversed upon administration of &mu-opioid receptor antagonist. Combined results demonstrate that endogenous opioids are the likely mediators responsible for attenuation of carcinoma-induced nociception with either ET-AR antagonist or ET-BR agonist.

      These novel findings suggest that there exist innate modulation of pain by SCCs involving endogenous opioids that can be exploited through manipulation of endothelin activity in the cancer micro-environment. Regulation of ET-AR or ET-BR signaling may be targets for future innovations for cancer pain management.

        Cover page: Endothelin Receptor-mediated Attenuation of Carcinoma-induced Nociception is Opioid-dependent in Mice
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2018)
        Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.
          Cover page: Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2017)
          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.

          Perspective

          We demonstrate that epigenetic regulation of OPRM1 contributes to opioid tolerance in cancer patients, and that targeted gene therapy could treat cancer-induced nociception and opioid tolerance in a mouse cancer model.
            Cover page: OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2018)
            Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.
              Cover page: Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation.
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2017)
              Widespread pain and anxiety are commonly reported in cancer patients. We hypothesize that cancer is accompanied by attenuation of endogenous opioid-mediated inhibition, which subsequently causes widespread pain and anxiety. To test this hypothesis we used a mouse model of oral squamous cell carcinoma (SCC) in the tongue. We found that mice with tongue SCC exhibited widespread nociceptive behaviors in addition to behaviors associated with local nociception that we reported previously. Tongue SCC mice exhibited a pattern of reduced opioid receptor expression in the spinal cord; intrathecal administration of respective mu (MOR), delta (DOR), and kappa (KOR) opioid receptor agonists reduced widespread nociception in mice, except for the fail flick assay following administration of the MOR agonist. We infer from these findings that opioid receptors contribute to widespread nociception in oral cancer mice. Despite significant nociception, mice with tongue SCC did not differ from sham mice in anxiety-like behaviors as measured by the open field assay and elevated maze. No significant differences in c-Fos staining were found in anxiety-associated brain regions in cancer relative to control mice. No correlation was found between nociceptive and anxiety-like behaviors. Moreover, opioid receptor agonists did not yield a statistically significant effect on behaviors measured in the open field and elevated maze in cancer mice. Lastly, we used an acute cancer pain model (injection of cancer supernatant into the mouse tongue) to test whether adaptation to chronic pain is responsible for the absence of greater anxiety-like behavior in cancer mice. No changes in anxiety-like behavior were observed in mice with acute cancer pain.
                Cover page: Alterations in opioid inhibition cause widespread nociception but do not affect anxiety-like behavior in oral cancer mice
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2014)

                Unlabelled

                Interindividual variability exists in persistent breast pain following breast cancer surgery. Recently, we used growth mixture modeling to identify 3 subgroups of women (N = 398) with distinct persistent breast pain trajectories (ie, mild, moderate, severe) over 6 months following surgery. The purposes of this study were to identify demographic and clinical characteristics that differed among the breast pain classes and, using linear mixed effects modeling, to examine how changes over time and in sensitivity in the breast scar area, pain qualities, pain interference, and hand and arm function differed among these classes. Several demographic and clinical characteristics differentiated the breast pain classes. Of note, 60 to 80% of breast scar sites tested were much less sensitive than the unaffected breast. Significant group effects were observed for pain qualities and interference scores, such that, on average, women in the severe pain class reported higher scores than women in the moderate pain class. In addition, women in the moderate pain class reported higher scores than women in the mild pain class. Compared to women in the mild pain class, women in the severe pain class had significantly impaired grip strength, and women in the moderate and severe pain classes had impaired flexion and abduction.

                Perspective

                Subgroups of women with persistent postsurgical breast pain differed primarily with respect to the severity rather than the nature or underlying mechanisms of breast pain. Pervasive sensory loss and the association between persistent breast pain and sustained interference with function suggest the need for long-term clinical follow-up.
                  Cover page: Persistent Breast Pain Following Breast Cancer Surgery Is Associated With Persistent Sensory Changes, Pain Interference, and Functional Impairments
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2013)
                  The purposes of this study were to evaluate for differences in phenotypic and genotypic characteristics in women who did and did not develop lymphedema (LE) following breast cancer treatment. Breast cancer patients completed a number of self-report questionnaires. LE was evaluated using bioimpedance spectroscopy. Genotyping was done using a custom genotyping array. No differences were found between patients with (n = 155) and without LE (n = 387) for the majority of the demographic and clinical characteristics. Patients with LE had a significantly higher body mass index, more advanced disease and a higher number of lymph nodes removed. Genetic associations were identified for four genes (i.e., lymphocyte cytosolic protein 2 (rs315721), neuropilin-2 (rs849530), protein tyrosine kinase (rs158689), vascular cell adhesion molecule 1 (rs3176861)) and three haplotypes (i.e., Forkhead box protein C2 (haplotype A03), neuropilin-2 (haplotype F03), vascular endothelial growth factor-C (haplotype B03)) involved in lymphangiogensis and angiogenesis. These genetic associations suggest a role for a number of lymphatic and angiogenic genes in the development of LE following breast cancer treatment.
                    Cover page: Lymphatic and angiogenic candidate genes predict the development of secondary lymphedema following breast cancer surgery.
                    • Article
                    • Peer Reviewed
                    UC San Francisco Previously Published Works (2016)
                    In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop.
                      Cover page: Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice
                      Top