Recent advances in developing opioid treatments for pain with reduced side effects have focused on the signaling cascades of the μ-opioid receptor (MOR). However, few such signaling targets have been identified for exploitation. To address this need, we explored the role of heat-shock protein 90 (Hsp90) in opioid-induced MOR signaling and pain, which has only been studied in four previous articles. First, in four cell models of MOR signaling, we found that Hsp90 inhibition for 24 h with the inhibitor 17--allylamino-17-demethoxygeldanamycin (17-AAG) had different effects on protein expression and opioid signaling in each line, suggesting that cell models may not be reliable for predicting pharmacology with this protein. We thus developed an model using CD-1 mice with an intracerebroventricular injection of 17-AAG for 24 h. We found that Hsp90 inhibition strongly blocked morphine-induced anti-nociception in models of post-surgical and HIV neuropathic pain but only slightly blocked anti-nociception in a naive tail-flick model, while enhancing morphine-induced precipitated withdrawal. Seeking a mechanism for these changes, we found that Hsp90 inhibition blocks ERK MAPK activation in the periaqueductal gray and caudal brain stem. We tested these signaling changes by inhibiting ERK in the above-mentioned pain models and found that ERK inhibition could account for all of the changes in anti-nociception induced by Hsp90 inhibition. Taken together, these findings suggest that Hsp90 promotes opioid-induced anti-nociception by an ERK mechanism in mouse brain and that Hsp90 could be a future target for improving the therapeutic index of opioid drugs.

Nociceptive sensitization is a common feature in chronic pain, but its basic cellular mechanisms are only partially understood. The present study used the model system and a candidate gene approach to identify novel components required for modulation of an injury-induced nociceptive sensitization pathway presumably downstream of Hedgehog. This study demonstrates that RNAi silencing of a member of the Bone Morphogenetic Protein (BMP) signaling pathway, Decapentaplegic (Dpp), specifically in the Class IV multidendritic nociceptive neuron, significantly attenuated ultraviolet injury-induced sensitization. Furthermore, overexpression of Dpp in Class IV neurons was sufficient to induce thermal hypersensitivity in the absence of injury. The requirement of various BMP receptors and members of the SMAD signal transduction pathway in nociceptive sensitization was also demonstrated. The effects of BMP signaling were shown to be largely specific to the sensitization pathway and not associated with changes in nociception in the absence of injury or with changes in dendritic morphology. Thus, the results demonstrate that Dpp and its pathway play a crucial and novel role in nociceptive sensitization. Because the BMP family is so strongly conserved between vertebrates and invertebrates, it seems likely that the components analyzed in this study represent potential therapeutic targets for the treatment of chronic pain in humans. This report provides a genetic analysis of primary nociceptive neuron mechanisms that promote sensitization in response to injury. larvae whose primary nociceptive neurons were reduced in levels of specific components of the BMP signaling pathway, were injured and then tested for nocifensive responses to a normally subnoxious stimulus. Results suggest that nociceptive neurons use the BMP2/4 ligand, along with identified receptors and intracellular transducers to transition to a sensitized state. These findings are consistent with the observation that BMP receptor hyperactivation correlates with bone abnormalities and pain sensitization in fibrodysplasia ossificans progressiva (Kitterman et al., 2012). Because nociceptive sensitization is associated with chronic pain, these findings indicate that human BMP pathway components may represent targets for novel pain-relieving drugs.

Chronic pain is a debilitating condition affecting millions of people worldwide, and an improved understanding of the pathophysiology of chronic pain is urgently needed. Nociceptors are the sensory neurons that alert the nervous system to potentially harmful stimuli such as mechanical pressure or noxious thermal temperature. When an injury occurs, the nociceptive threshold for pain is reduced and an increased pain signal is produced. This process is called nociceptive sensitization. This sensitization normally subsides after the injury is healed. However, dysregulation can occur which results in sensitization that persists after the injury has healed. This process is thought to perpetuate chronic pain. The Hedgehog (Hh) signaling pathway has been previously implicated in nociceptive sensitization in response to injury in Drosophila melanogaster. Downstream of Hh signaling, the Bone Morphogenetic Protein (BMP) pathway has also been shown to be necessary for this process. Here, we describe a role for nuclear components of BMP’s signaling pathway in the formation of injury-induced nociceptive sensitization. Brinker (Brk), and Schnurri (Shn) were suppressed in nociceptors using an RNA-interference (RNAi) “knockdown” approach. Knockdown of Brk resulted in hypersensitivity in the absence of injury, indicating that it normally acts to suppress nociceptive sensitivity. Animals in which transcriptional activator Shn was knocked down in nociceptors failed to develop normal allodynia after ultraviolet irradiation injury, indicating that Shn normally acts to promote hypersensitivity after injury. These results indicate that Brk-related transcription regulators play a crucial role in the formation of nociceptive sensitization and may therefore represent valuable new targets for pain-relieving medications.

Over 100 million people are challenged by the effects of chronic pain in the United States alone. This burden also impacts the U.S. economy; 600 billion dollars annually is spent on medical care, medications, and lost productivity in the workplace. Current opioid treatments cause adverse effects including nausea, constipation, tolerance, and addiction liability. Nociceptive sensitization is thought to perpetuate chronic pain, but too little is known about its mechanisms. Components of the pathways that sensitize the nociceptors after injury are likely to be valuable targets for novel medications for the relief or prevention of chronic pain. Utilizing the Drosophila melanogaster cell targeting and RNA interference toolkit, we are investigating the bone morphogenetic protein pathway and its role in ultraviolet light injury-induced nociceptive sensitization. Bone morphogenetic proteins are well known as secreted developmental morphogens that control development, but other functions are known. We have previously identified bone morphogenetic protein signaling components used in nociceptors to modulate injury-induced allodynia, including Decapentaplegic (Dpp, orthologous to mammalian bone morphogenetic protein 2/4), and its downstream signaling components. The morphogen Hedgehog has also been shown to be necessary for allodynia following injury. Here, we show that two membrane-embedded regulators of the Dpp and Hedgehog pathways, Dally and Dally-like, are necessary for injury-induced thermal allodynia, as the formation of sensitization was reduced when either component was suppressed. These bone morphogenetic protein components are highly conserved and, because dysregulation of nociceptor sensitization underlies chronic pain, the homologs of Dally and Dally-like may represent novel therapeutic targets in humans challenged by chronic pain. Furthermore, because of their extracellular location, Dally and Dally-like represent attractive therapeutic drug targets because such drugs would not need to cross the plasma membrane.

241 Background: Reducing ED visits in patients with cancer is cost saving and is particularly relevant during the COVID pandemic. We aim to identify patterns of ED visits among various cancer patients and reduce preventable ED visits and hospital admissions. Methods: We analyzed the number of ED visits and hospital admissions that occurred in patients with breast, lung, and Gastrointestinal (GI) cancers between July12019 and October31 2020 including demographics, stage, treatment type preceding the month of ED visit, reason, time of the day, day of the week the visit occurred. Results: 308 patients had 519 ED visits, 111 breast cancer patients had 184, 102 lung cancer patients had 186 and 95 GI cancer patients had 149 ED visits. 38% had > 1 visit. 51%, (37% breast, 60% Lung and 58 % GI cancer) had stage 4 disease at the time of visit. There were no visits in the month of May 2020. 275 (53%) visits required hospital admissions, 60% of ED visits in lung cancer, 54% in GI and 46 % in breast cancer patients required hospitalization. Most common reason for ED visits in breast cancer patients was fall/injury (20%), with median age of 71 years, none were cancer/ chemotherapy induced. Among lung and GI cancer patients respiratory (24%) and GI related (24%) symptoms were the most common reasons respectively, majority were cancer/chemotherapy related. Most common symptoms requiring hospital admissions were respiratory 21%, GI 18%, cardiac 12%. 11% and 9% of ED visits were due to fall/injury and cancer related pain, of these 3.6% and 9% resulted in hospital admissions respectively. Lung and GI cancer patients were more likely to be referred to the ED from the oncologist office (23%) than breast cancer patients (11%). Conclusions: Reasons for ED visits vary by tumor types and some may be preventable. Fall/injury in breast cancer patients and cancer related pain in lung and GI cancer patients were frequent reasons for preventable ED visits. In lung and GI cancer patients, cancer/chemotherapy related respiratory, GI symptoms are felt to be less avoidable since they may be related to disease progression or presenting symptoms. We have initiated several strategies such as ‘’systematic physical therapy assessment’’ of our breast cancer patients over age 70 to reduce ED visits due to fall/injury. We are developing strategies to involve palliative care early to reduce the number of ED visits related to cancer related pain We now have “call us first campaign” to assess and intervene before going to ED since most visits occurred during working hours.[Table: see text]