An opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish (Danio rerio) is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by mu-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.
An opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish (Danio rerio) is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by mu-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.
ObjectivesOutpatient in-person early palliative care improves quality of life for patients with advanced cancer. The COVID-19 pandemic forced a rapid shift to telehealth visits; however, little is known about how telehealth in outpatient palliative care settings should be optimised beyond the pandemic. We aimed to explore, from the perspective of patients attending an outpatient palliative care clinic, the most appropriate model of care for in-person versus telehealth visits.MethodsA qualitative study using the grounded theory method. One-on-one, semistructured qualitative interviews were conducted with 26 patients attending an outpatient palliative care clinic at a tertiary cancer centre recruited from two groups: (1) those with >1 in-person appointment prior to 1 March 2020 and >1 telehealth appointment after this date (n=17); and (2) patients who had exclusively telehealth appointments (n=9). Purposive sampling was used to incorporate diverse perspectives.ResultsOverall, participants endorsed a flexible hybrid approach incorporating both in-person and telehealth visits. Specific categories were: (1) in-person outpatient palliative care supported building interpersonal connections and trust; (2) telehealth palliative care facilitated greater efficiency, comfort and independence and (3) patient-preferred circumstances for in-person visits (preferred for initial consultations, visits where a physical examination may be required and advance care planning discussions), versus telehealth visits (preferred during periods of relative heath stability).ConclusionsThe elements of in-person and telehealth outpatient palliative care clinic visits described by patients as integral to their care may be used to develop models of hybrid outpatient palliative care delivery beyond the pandemic alongside reimbursement and regulatory guidelines.
IntroductionOpioid drugs are the mainstay of pain management, but their use is limited by their severe side‐effects that can be lethal with overdose. Indeed, opioid drugs induce respiratory depression, that can lead to severe hypoxemia and respiratory arrest when opioids are abused. The current antidote naloxone (Narcan) is a life‐saving therapy, but its use is limited because it can only be given after the overdose occurs, so it is not a preventive treatment. The main challenge in opioid drug discovery is therefore to develop new opioid therapies with potent analgesia but reduced respiratory depression, so opioids can be safely prescribed.ObjectivesTo accelerate drug discovery, we established phenotype‐based approaches using in vivo zebrafish models of respiratory depression and analgesia. Zebrafish is an amenable model to study respiratory depression because its respiratory circuits are similar to mammalian circuits. Also, zebrafish μ‐opioid receptors have 70% homology of amino acids with their mammalian counterparts. Our aim was to developed a high‐throughput screening platform that combines drug screening and behavioural profiling so new preventive therapies can be identified.MethodsTo determine respiratory depression, we assessed buccal movements, as an index of respiratory activity, in zebrafish larvae (day post‐fertilization 14), and its response to the μ‐opioid receptor analgesic fentanyl. We used a video‐recording system to assess zebrafishes in multi‐well plate. To assess opioid analgesia, we induced mild pain in zebrafish larvae by submerging it in a solution of formalin, or formalin/fentanyl, and measuring its subsequent locomotor or swimming response.ResultsFentanyl (0.02 μM) significantly decreased the rate of buccal movements by 84% (baseline 41.7 breath/min, fentanyl 6.71 breath/min, n=11, p=0.038), a depression reversed by naloxone (5 μM, 44.3 breath/min, p=0.01). Similarly, respiratory depression by fentanyl was reversed by the AMPA receptor modulator ampakine CX‐614 (50 μM, p=0.04, n=10) and the 5‐HT4 agonist BIMU‐8 (10 μM, n=6, p=0.035). Formalin (0.05%) increased increased locomotion, and this response was significantly reduced by fentanyl (1 μM), an analgesic effect blocked by naloxone (5 μM).DiscussionOur novel and unique zebrafish models mimicked well the effects of opioid drugs on respiratory activity and nociception observed in mammals. This proof‐of‐principle study suggests that zebrafish can be used for phenotype‐based high‐throughput drug and gene screening. Using these assays, we will knock‐down key‐genes involved in opioid inhibition using morpholino oligonucleotides, and test chemical screens to identify preventive therapies to minimize respiratory depression by opioids while preserving their analgesic properties.Support or Funding InformationSt. Michael's Hospital FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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