Inflammatory pain is a key component of acute traumatic pain and chronic rheumatic disease, which significantly reduces the quality of life of those who suffer from it and is often refractory to treatment. One contributor to the failure of current treatments is that the majority of pain testing has historically been performed in male subjects while the majority of pain patients are women. To better manage inflammatory pain, first the baseline sex differences in its experience must be assessed. Therefore, we evaluated C57BL/6J male and female mice for baseline sex differences in the formalin model of inflammatory pain, further investigating the observed significant sex differences through both assessing female mice at each phase of the estrous cycle and through examining the effects of gonadectomy (ovariectomy or castration) within the formalin model of inflammatory pain. Female mice in the metestrus or diestrus phase had decreased inflammatory pain relative to both male mice and female mice in the proestrus or estrus phase. Ovariectomy resulted in decreased pain, which was restored through treatment with estradiol (E2). Castration similarly reduced pain in male mice. Injection of the G-protein coupled estrogen receptor (GPER) agonist G1 resulted in significant antinociception in both female and male mice, in both mice that had received sham surgery or gonadectomy. These results establish baseline sex differences in the formalin model of inflammatory pain and support the need for further investigation into the interaction between estrogen, its receptors, and testosterone in the regulation of nociception.

BACKGROUND:Breast cancer represents the most common cancer diagnosis and the leading cause of cancer-related death in women. Cancer is also associated with pain and changes in both tactile and temperature sensitivity that impair quality of life. While previous studies have investigated the effects of various chemotherapies in murine models of these symptoms, few have previously assessed the effects of cancer alone on these symptoms. METHODS:We evaluated the efficacy of murine AT-3 and E0771 breast cancer cell lines on the rate of tumour growth using the Von Frey test (mechanical sensitivity/allodynia) and the acetone test (cold sensitivity/allodynia) in female C57BL/6J wild-type mice. Evaluations for changes in oestrous cycle and mRNA expression in both tumour and whole brain tissue were then performed. RESULTS:While both cancer cell lines induced significant tumour growth, this growth was significantly greater in the AT-3 cell line than in the E0771 cell line. The AT-3 cell line significantly decreased mechanical and cold sensitivity (allodynia) and significantly altered the oestrous cycle to increase the time spent in a low oestrogen phase (oestrus). In comparison, the E0771 cell line significantly decreased mechanical and cold sensitivity (allodynia) without oestrous cycle alterations. When comparing gene expression in tumour tissue between the two cell lines, the E0771 cell line significantly increased expression of fatty acid amide hydrolase and calcitonin receptor-like. CONCLUSIONS:These results demonstrate the significant impacts of breast cancer on mechanical and cold sensitivity and support the need for further investigations into possible interactions between cancer and chemotherapy in these modalities. SIGNIFICANCE STATEMENT:Cancer-associated pain and altered sensations significantly decrease patient quality of life. In our murine model, we have shown that breast cancer cell lines (AT-3 and E0771) alter mechanical and cold sensitivity. These changes coincided with oestrous cycle changes (AT-3) and mRNA expression changes (E0771). A better understanding of our findings will elucidate different mechanisms of action while identifying preventative strategies and potential interactions with chemotherapy.

Abstract ID 92528Poster Board 501Cannabinoid-based therapies potentially offer a safer, non-opioid alternative for the management of chronic pain, but tolerance to cannabinoids like delta-9-tetrahydrocannabinol (Δ9-THC) may limit their therapeutic utility. Blocking peroxiredoxin 6 (PRDX6) activation has been shown to attenuate the development of morphine tolerance, and PRDX6 activation in morphine tolerance is at least partially mediated through phosphorylation by c-Jun N-terminal kinase (JNK). JNK signaling has also been shown to modulate tolerance to the antinociceptive effects of cannabinoids, including Δ9-THC and CP55,940, in an agonist-specific manner. As such, the purpose of this study was to determine whether pharmacological inhibition or genetic disruption of PRDX6 would alter Δ9-THC- and/or CP55,940-induced antinociception and/or tolerance. The acute antinociceptive dose response effects of Δ9-THC (0 to 100 mg/kg) or CP55,940 (0 to 1.0 mg/kg) were tested across a range of doses using the tail-flick test. The dose response effects of these cannabinoids on hypothermia was also measured. Consistent with previous findings in our lab, male mice were, overall, more sensitive to the antinociceptive effects of Δ9-THC than female mice. Across both sexes, KO mice exhibited a decreased acute antinociceptive response to Δ9-THC (but not CP55,940) compared to their WT counterparts. Cannabinoid-induced hypothermia did not differ as a function of genotype. Male C57Bl/6 mice pretreated with the PRDX6 antagonist, MJ33 (1.25 mg/kg) and male PRDX6 KO mice were also assessed for tolerance to Δ9-THC-mediated antinociception and hypothermia. In contrast to our hypothesis, inhibition of PRDX6 using genetic or pharmacological approaches blunts Δ9-THC-mediated antinociception. However, no difference in tolerance to the effects of Δ9-THC was detected in either PRDX6 KO or MJ33-treated WT mice compared to WT or vehicle-treated WT controls. These results suggest that PRDX6 likely plays a role in modulating Δ9-THC-induced antinociception, and future studies should examine whether these changes are mediated through JNK-dependent pathways.This research was supported by NIDA Grant R01DA044999.

Inflammatory pain is caused by tissue hypersensitization and is a component of rheumatic diseases, frequently causing chronic pain. Current guidelines use a multimodal approach to pain and sociocultural changes have renewed interest in cannabinoid use, particularly cannabidiol (CBD), for pain. The tricyclic antidepressant amitriptyline (AT) is approved for use in pain-related syndromes, alone and within a multimodal approach. Therefore, we investigated sex- and dose-dependent effects of CBD and AT antinociception in the 2.5% formalin inflammatory pain model. Male and female C57BL/6J mice were pretreated with either vehicle, CBD (0.3-100 mg/kg), or AT (0.1-30 mg/kg) prior to formalin testing. In the acute phase, CBD induced antinociception after administration of 30-100 mg/kg in males and 100 mg/kg in females and in the inflammatory phase at doses of 2.5-100 mg/kg in males and 10-100 mg/kg in females. In the acute phase, AT induced antinociception at 10 mg/kg for all mice, and at 0.3 mg/kg in males and 3 mg/kg in female mice in the inflammatory phase. Combining the calculated median effective doses of CBD and AT produced additive effects for all mice in the acute phase and for males only in the inflammatory phase. Use of selective serotonin 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635) maleate (0.1 mg/kg) before co-administration of CBD and AT reversed antinociception in the acute and partially reversed antinociception in the inflammatory phase. Administration of AT was found to enhance cannabinoid receptor type 1mRNA expression only in female mice. These results suggest a role for serotonin and sex in mediating cannabidiol and amitriptyline-induced antinociception in inflammatory pain. SIGNIFICANCE STATEMENT: Inflammatory pain is an important component of both acute and chronic pain. We have found that cannabidiol (CBD) and amitriptyline (AT) show dose-dependent, and that AT additionally shows sex-dependent, antinociceptive effects in an inflammatory pain model. Additionally, the combination of CBD and AT was found to have enhanced antinociceptive effects that is partially reliant of serotonin 1A receptors and supports the use of CBD within a multimodal approach to pain.

Abstract ID 95376Poster Board 503Cannabinoids offer a promising analgesic treatment option for a variety of pain conditions, but their chronic use leads to the development of tolerance to the antinociceptive effects, posing a problem to their utilization as an effective long-term therapeutic. Agonist-induced internalization of cannabinoid receptor 1 (CB1R) is a crucial component in regulating signal transduction and the C-terminus tail of CB1R serves as a regulatory domain for internalization. Six point mutant (6PM) mice express serine/threonine to alanine point mutations for six putative G protein-coupled receptor kinase (GRK) phosphorylation sites in the C-terminus tail of CB1Rs that are necessary for internalization, thereby making the CB1Rs unable to efficiently undergo internalization, trafficking, and resensitization. The objective of this study is to investigate the effect of CB1R internalization on sensitivity to the acute antinociceptive and hypothermic effects of cannabinoid agonists as well as assessing recognition memory and motor coordination in 6PM mice expressing an internalization-deficient form of CB1R. A cumulative dose response curve was used to assess the acute response to CP55,940, a strongly internalizing cannabinoid agonist. Antinociception was measured using the tail-flick test and cannabinoid-induced hypothermia was examined by recording core body temperature. Motor coordination was assessed using the rotarod test where the latency to fall was measured. Recognition memory was evaluated using the novel object recognition (NOR) test where novel object recognition was determined by measuring time exploring a familiar versus a novel object placed in the test arena. 6PM mice show decreased antinociceptive and hypothermic responses to the effects of CP55,940 compared to wild-type controls. 6PM mice also displayed a decrease in recognition memory by spending more time exploring the familiar object, rather than the novel object in the novel object recognition test relative to wild-type controls. There were no differences between wild-type and 6PM mice in the average time spent on the rotarod. Data from this study demonstrate that the antinociceptive and hypothermic effects of CP55,940 were reduced in the 6PM mice suggesting that CB1R internalization, trafficking, and recycling may be important components involved in the response to cannabinoids. This data also shows that six point mutant mice have a lower recognition memory, indicating a possible role for CB1R internalization in cognitive processes. Overall, these results suggest that internalization may be a critical regulator of responses to cannabinoids as well as playing a role in memory formation and recall pathways.Acknowledgements Funded by NIH grant DA044999 and the NASA West Virginia Space Grant Consortium, Grant # 80NSSC20M0055.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB1)-selective, cannabinoid receptor type 2 (CB2)-selective, and CB1/CB2 mixed agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. SIGNIFICANCE STATEMENT CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.

Cannabis has been used recreationally and medically for centuries, yet research into understanding the mechanisms of its therapeutic effects has only recently garnered more attention. There is evidence to support the use of cannabinoids for the treatment of chronic pain, muscle spasticity, nausea and vomiting due to chemotherapy, improving weight gain in HIV-related cachexia, emesis, sleep disorders, managing symptoms in Tourette syndrome, and patient-reported muscle spasticity from multiple sclerosis. However, tolerance and the risk for cannabis use disorder are two significant disadvantages for cannabinoid-based therapies in humans. Recent work has revealed prominent sex differences in the acute response and tolerance to cannabinoids in both humans and animal models. This review will discuss evidence demonstrating cannabinoid tolerance in rodents, non-human primates, and humans and our current understanding of the neuroadaptations occurring at the cannabinoid type 1 receptor (CB1R) that are responsible tolerance. CB1R expression is downregulated in tolerant animals and humans while there is strong evidence of CB1R desensitization in cannabinoid tolerant rodent models. Throughout the review, critical knowledge gaps are indicated and discussed, such as the lack of a neuroimaging probe to assess CB1R desensitization in humans. The review discusses the intracellular signaling pathways that are responsible for mediating CB1R desensitization and downregulation including the action of G protein-coupled receptor kinases, β-arrestin2 recruitment, c-Jun N-terminal kinases, protein kinase A, and the intracellular trafficking of CB1R. Finally, the review discusses approaches to reduce cannabinoid tolerance in humans based on our current understanding of the neuroadaptations and mechanisms responsible for this process.

Tolerance to compounds that target G protein–coupled receptors (GPCRs), such as the cannabinoid type-1 receptor (CB1R), is in part facilitated by receptor desensitization. Processes that mediate CB1R desensitization include phosphorylation of CB1R residues S426 and S430 by a GPCR kinase and subsequent recruitment of the β-arrestin2 scaffolding protein. Tolerance to cannabinoid drugs is reduced in S426A/S430A mutant mice and β-arrestin2 knockout (KO) mice according to previous work in vivo. However, the presence of additional phosphorylatable residues on the CB1R C-terminus made it unclear as to whether recruitment to S426 and S430 accounted for all desensitization and tolerance by β-arrestin2. Therefore, we assessed acute response and tolerance to the cannabinoids delta-9-tetrahydrocannabinol (Δ9-THC) and CP55,940 in S426A/S430A x β-arrestin2 KO double-mutant mice. We observed both delayed tolerance and increased sensitivity to the antinociceptive and hypothermic effects of CP55,940 in male S426A/S430A single- and double-mutant mice compared with wild-type littermates, but not with Δ9-THC. Female S426A/S430A single- and double-mutant mice were more sensitive to acute antinociception (CP55,940 and Δ9-THC) and hypothermia (CP55,940 only) exclusively after chronic dosing and did not differ in the development of tolerance. These results indicate that phosphorylation of S426 and S430 are likely responsible for β-arrestin2–mediated desensitization as double-mutant mice did not differ from the S426A/S430A single-mutant model in respect to cannabinoid tolerance and sensitivity. We also found antinociceptive and hypothermic effects from cannabinoid treatment demonstrated by sex-, agonist-, and duration-dependent features. SIGNIFICANCE STATEMENT A better understanding of the molecular mechanisms involved in tolerance will improve the therapeutic potential of cannabinoid drugs. This study determined that further deletion of β-arrestin2 does not enhance the delay in cannabinoid tolerance observed in CB1R S426A/S430A mutant mice.

Economic and societal impact of cancer is tremendous, accounting, in 2022, for nearly 10 million deaths worldwide. Development of new safe and effective treatments that improve cancer therapy and alleviate chemotherapy-induced peripheral neuropathy (CIPN) side effects of treatment with chemotherapeutic agents remains an important clinical need. Cannabis has been used for more than 12,000 years for different purposes. Recent softening of prior social stigma around the use of cannabis and legalization of medical cannabis in 37 states has led to increase use in recreational and medical cannabis. Indeed, cannabinoid-based therapies are increasingly being used by cancer patients to treat chemotherapy-induced nausea/vomiting and alleviate CIPN. However, only few preclinical and clinical studies have investigated the impact of cannabinoids compounds in tumor growth. Further studies are needed to establish the role of cannabinoid compounds in tumor growth since their beneficial effect of alleviating CIPN could negatively influence tumor growth.

Cannabinoids are increasingly used to alleviate pain; however, tolerance to their antinociceptive effects, including those of delta-9-tetrahydrocannabinol (Δ9-THC), may limit their therapeutic utility. With more women than men using medical cannabis for pain relief, it is crucial to understand how sex influences cannabinoid-mediated antinociception and tolerance. Though studies in rats consistently find females are more sensitive to the acute antinociceptive effects of cannabinoids, our work with mice consistently finds the converse. The present study examined whether our observed sex differences in Δ9-THC-induced antinociception and tolerance are consistent across multiple mouse strains or are strain-dependent. Male and female C57BL/6J (B6), DBA/2, AKR, and CBA/J mice were assessed for differences in acute Δ9-THC-induced antinociception and hypothermia prior to and following seven days of once-daily Δ9-THC administration. Consistent with our previous findings, male B6 mice were more sensitive to the acute antinociceptive effects of Δ9-THC than female littermates, an effect which dissipated with age. B6 males had decreased cannabinoid expression in the PAG compared to females. While DBA and CBA female mice showed increased Δ9-THC-antinociception compared to male littermates at 30 and 10 mg/kg Δ9-THC, respectively, these differences were less pronounced at higher doses, revealing that dose of Δ9-THC may also be important. Overall, CBA mice were more sensitive to Δ9-THC-induced antinociception while AKR mice were less responsive. These studies highlight the therapeutic potential of Δ9-THC in pain management and underscore the importance of considering not only Δ9-THC dose as a function of sex, but potentially genetic differences when evaluating their clinical utility.

Cardiovascular disease represents a leading cause of death, morbidity, and societal economic burden. The prevalence of cannabis use has significantly increased due to legalization and an increased societal acceptance of cannabis. Therefore, it is critically important that we gain a greater understanding of the effects and risks of cannabinoid use on cardiovascular diseases as well as the potential for cannabinoid-directed drugs to be used as therapeutics for the treatment of cardiovascular disease. This review summarizes our current understanding of the role of cannabinoid receptors in the pathophysiology of atherosclerosis and myocardial ischemia and explores their use as therapeutic targets in the treatment of ischemic heart disease. Endocannabinoids are elevated in patients with atherosclerosis, and activation of cannabinoid type 1 receptors (CB1Rs) generally leads to an enhancement of plaque formation and atherosclerosis. In contrast, selective activation of cannabinoid type 2 receptors (CB2Rs) appears to exert protective effects against atherosclerosis. Endocannabinoid signaling is also activated by myocardial ischemia. CB2R signaling appears to protect the heart from ischemic injury, whereas the role of CB1R in ischemic injury is less clear. This narrative review serves to summarize current research on the role of cannabinoid signaling in cardiovascular function with the goal of identifying critical knowledge gaps and future studies to address those gaps in a way that facilitates the development of new treatments and better cardiovascular health. SIGNIFICANCE STATEMENT: Cardiovascular diseases, including atherosclerosis and myocardial infarction, are a leading cause of death. Cannabinoid drugs have well known acute effects on cardiovascular function, including tachycardia and orthostatic hypotension. The recent legalization of marijuana and cannabinoids for both medical and recreational use has dramatically increased their prevalence of use. This narrative review on the role of cannabinoid signaling in cardiovascular disease contributes to a better understanding of this topic by integrating current knowledge and identifying critical gaps.

Chronic pain is one of the most common, costly, and potentially debilitating health issues facing older adults, with attributable costs exceeding $600 billion annually. The prevalence of pain in humans increases with advancing age. Yet, the contributions of sex differences, age-related chronic inflammation, and changes in neuroplasticity to the overall experience of pain are less clear, given that opposing processes in aging interact. This review article examines and summarizes pre-clinical research and clinical data on chronic pain among older adults to identify knowledge gaps and provide the base for future research and clinical practice. We provide evidence to suggest that neurodegenerative conditions engender a loss of neural plasticity involved in pain response, whereas low-grade inflammation in aging increases CNS sensitization but decreases PNS sensitivity. Insights from preclinical studies are needed to answer mechanistic questions. However, the selection of appropriate aging models presents a challenge that has resulted in conflicting data regarding pain processing and behavioral outcomes that are difficult to translate to humans.

Cannabinoid-based therapies are increasingly being used by cancer patients to treat chemotherapy-induced nausea and vomiting. Recently, cannabinoids have gained increased attention for their effects on cancer growth. Indeed, the effect of CB2 (JWH-015, JWH-133) agonists on breast cancer models have shown to reduce the size of breast cancer tumors. However, these studies assessing breast cancer progression were using CB2 agonist administered early into the cancer progression therefore assessing their effects on already established tumors is a critical need. In our study, we evaluate tumor growth using an ectopic xenograft ovarian (SKOV-3 and OVCAR-5) cancer model. The impact of chronic (30 days) administration of CB2 (JWH-133) agonist will be evaluated and started on 30 days of ectopic ovarian tumors. We will then evaluate and determine the mechanisms involved in ovarian cancer tumor growth by measuring levels of anandamide and 2-arachidonoyl glycerol as well as protein levels of CB1, CB2, ERα, ERβ, GPER, TNFα, IL-1β and IL-6 in ovarian and tumor tissues. Our results demonstrate a significant increase in ectopic ovarian tumor growth following chronic administration of JWH-133. Ovarian cancer tumor tissues chronically (30 days) treated with JWH-133 in comparison to vehicle treated groups showed an increase in endocannabinoid (AEA and 2-AG) and protein (CB2 and TNFα) levels with a decrease in GPER protein levels. Interestingly, our study emphasizes the importance of studying the impact of cannabinoid compounds on already established tumors to improve our understanding of cannabinoid-based therapies and, therefore better address clinical needs in cancer patients.

Activation of c-Jun N-terminal kinases (JNKs) has been implicated in the development and persistence of inflammatory and neuropathic pain in animal models. Moreover, JNKs have been involved in the maintenance of chronic pain, as well as development of tolerance to antinociceptive agents in the opioid and cannabinoid class of compounds. In this study, we evaluated the antinociceptive effects of the JNK inhibitor SU 3327 (0.3-30 mg/kg) in the formalin pain model with an emphasis on the sex-specific actions of this compound. In wild-type C57BL6J mice, SU 3327 produced strong antinociceptive effects in the formalin pain model which were mediated by CB2 receptors in females, and both CB1 and CB2 receptors in males. SU 3327 at a dose of 10 mg/kg produced antinociception, hypothermia, motor impairment, and hypolocomotion to a similar extent in both males and females. The antinociceptive effects of SU 3327 were more potent in males at lower doses (1 and 3 mg/kg), while females were more sensitive to the hypothermic, and motor-suppression effects at lower (3 mg/kg) doses versus males. Analysis of spinal cords, using qPCR following SU 3327 administration in the formalin test, revealed changes in cannabinoid, tolerance and inflammatory markers in females only, and only in the high (10-30 mg/kg) dose conditions. Indeed, females showed an increase in mRNA levels of cannabinoid (CB2), but a decrease in tolerance (beta-arrestin 1) and inflammatory (TNF-alpha, IL-1 beta, IL-6)-associated markers. The differences between males and females, in this study, support sex as an important factor in nociception and antinociceptive responses mediated by JNK and the endocannabinoid system.

Cannabis use has been increasing in recent years, particularly among women, and one of the most common uses of cannabis for medical purposes is pain relief. Pain conditions and response to analgesics have been demonstrated to be influenced by sex, and evidence is emerging that this is also true with cannabinoid-mediated analgesia. In this review we evaluate the preclinical evidence supporting sex differences in cannabinoid pharmacology, as well as emerging evidence from human studies, both clinical and observational. Numerous animal studies have reported sex differences in the antinociceptive response to natural and synthetic cannabinoids that may correlate to sex differences in expression, and function, of endocannabinoid system components. Female rodents have generally been found to be more sensitive to the effects of Δ9-THC. This finding is likely a function of both pharmacokinetic and pharmacodynamics factors including differences in metabolism, differences in cannabinoid receptor expression, and influence of ovarian hormones including estradiol and progesterone. Preclinical evidence supporting direct interactions between sex hormones and the endocannabinoid system may translate to sex differences in response to cannabis and cannabinoid use in men and women. Further research into the role of sex in endocannabinoid system function is critical as we gain a deeper understanding of the impact of the endocannabinoid system in various disease states, including chronic pain.

Dishevelled (DVL) critically regulates Wnt signaling and contributes to a wide spectrum of diseases and is important in normal and pathophysiological settings. However, how it mediates diverse cellular functions remains poorly understood. Recent discoveries have revealed that constitutive Wnt pathway activation contributes to breast cancer malignancy, but the mechanisms by which this occurs are unknown and very few studies have examined the nuclear role of DVL. Here, we have performed DVL3 ChIP-seq analyses and identify novel target genes bound by DVL3. We show that DVL3 depletion alters KMT2D binding to novel targets and changes their epigenetic marks and mRNA levels. We further demonstrate that DVL3 inhibition leads to decreased tumor growth in two different breast cancer models in vivo. Our data uncover new DVL3 functions through its regulation of multiple genes involved in developmental biology, antigen presentation, metabolism, chromatin remodeling, and tumorigenesis. Overall, our study provides unique insight into the function of nuclear DVL, which helps to define its role in mediating aberrant Wnt signaling.

According to the National Cancer Institute in 2020 there will be an estimated 21,750 new ovarian cancer cases and 276,480 new breast cancer cases. Both breast and ovarian cancer are hormone dependent cancers, meaning they cannot grow without the presence of hormones. The two most studied hormones in these two cancers are estrogen and progesterone, which are also involved in the modulation of pain. The incidence of pain in breast and ovarian cancer is very high. Research about mechanisms involved in modulation of pain by hormones are still being debated, as some studies find estrogen to be anti-nociceptive and others pro-nociceptive in pain studies. Moreover, analgesic treatments for breast and ovarian cancer-associated pain are limited and often ineffective. In this review, we will focus on estrogen and progesterone mechanisms of action in modulation of pain and cancer. We will also discuss new treatment options for these types of cancer and associated-pain.