RESUMO
BACKGROUND: Postoperative pneumothorax is a well-known but relatively rare complication after laparoscopic surgery. There has been no report describing pneumothorax that persisted for a week or more after laparoscopic surgery. Herein, we report a case of bilateral pneumothorax after laparoscopic surgery, which appears to have occurred by a different mechanism than previously described. CASE PRESENTATION: A 65-year-old male, with a past history of esophagectomy and retrosternal gastric tube reconstruction 4 months earlier, underwent a robotic-assisted inguinal hernia repair. Postoperative chest x-rays revealed the development of bilateral pneumothorax, which became worse on postoperative day (POD) 1 and took more than 9 days to resolve spontaneously. We assumed that intra-abdominal gas replaced by the air after pneumoperitoneum might have migrated into thoracic cavities through an opened esophageal hiatus or along the retrosternal route. CONCLUSIONS: Laparoscopic surgery after radical esophagectomy may be associated with an increased risk of postoperative pneumothorax.
RESUMO
BACKGROUND: Transdermal fentanyl is widely used in the treatment of severe pain because of convenience, safety, and stable blood concentrations. Nevertheless, patients often develop tolerance to fentanyl, necessitating the use of other opioids; transdermal buprenorphine patch is widely used as an analgesic agent, though available formulation does not provide comparable analgesic effect as transdermal fentanyl patch. Opioids bind to the opioid receptor (OR) to activate both G protein-mediated and ß-arrestin-mediated pathways. We synthesized morphine-related compounds with high transdermal absorbability (N1 and N2) and evaluated their OR activities pharmacologically in comparison with fentanyl and morphine. METHODS: In cells stably expressing µ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR), G protein-mediated pathways were assessed using the CellKey and an intracellular cyclic adenosine monophosphate (cAMP) assay, while ß-arrestin-mediated pathways were analyzed with ß-arrestin recruitment and receptor internalization assays. Furthermore, analgesic effects were evaluated using a tail-flick test in mice, and the analgesic effect on fentanyl-tolerant mice was evaluated. RESULTS: In the CellKey and cAMP assays, both N1 and N2 showed the highest affinity for MOR and acted as full agonists as well as partial agonists for DOR and KOR. In the ß-arrestin and internalization assays, only fentanyl acted as a full agonist; N1 and N2 acted as partial agonists of MOR. In the mouse tail-flick test, N1 and N2 showed analgesic effects equivalent to those of fentanyl and morphine. In fentanyl-tolerant mice, fentanyl showed a diminished analgesic effect, whereas N1 and N2 as well as morphine retained their analgesic effects. CONCLUSIONS: While N1 and N2 have higher transdermal absorbability than fentanyl, they also have analgesic effects comparable to those of morphine, suggesting that they may be attractive compounds for the development of novel opioid patches for transitioning from fentanyl patches.
Assuntos
Fentanila , Morfina , Analgésicos Opioides , Animais , Proteínas de Ligação ao GTP/metabolismo , Humanos , Camundongos , Receptores Opioides/metabolismo , Receptores Opioides mu/agonistas , beta-Arrestinas/metabolismoRESUMO
The issue of tolerance to continuous or repeated administration of opioids should be addressed. The ability of ketamine to improve opioid tolerance has been reported in clinical studies, and its mechanism of tolerance may involve improved desensitization of µ-opioid receptors (MORs). We measured changes in MOR activity and intracellular signaling induced by repeated fentanyl and morphine administration and investigated the effects of ketamine on these changes with human embryonic kidney 293 cells expressing MOR using the CellKey™, cADDis cyclic adenosine monophosphate, and PathHunter® ß-arrestin recruitment assays. Repeated administration of fentanyl or morphine suppressed the second MOR responses. Administration of ketamine before a second application of opioids within clinical concentrations improved acute desensitization and enhanced ß-arrestin recruitment elicited by fentanyl but not by morphine. The effects of ketamine on fentanyl were suppressed by co-treatment with an inhibitor of G-protein-coupled receptor kinase (GRK). Ketamine may potentially reduce fentanyl tolerance but not that of morphine through modulation of GRK-mediated pathways, possibly changing the conformational changes of ß-arrestin to MOR.
Assuntos
Ketamina , Morfina , Analgésicos Opioides/farmacologia , Tolerância a Medicamentos , Fentanila/farmacologia , Humanos , Ketamina/farmacologia , Morfina/farmacologia , Receptores Opioides/metabolismo , beta-Arrestinas/metabolismoRESUMO
Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the ß-arrestin-mediated pathway, which leads to unfavorable side effects. Hence, G-protein-biased opioid agonists are preferable as opioid analgesics. Rubiscolins, the spinach-derived naturally occurring opioid peptides, are selective δ opioid receptor agonists, and their p.o. administration exhibits antinociceptive effects. Although the potency and effect of rubiscolins as G-protein-biased molecules are partially confirmed, their in vitro profiles remain unclear. We, therefore, evaluated the properties of rubiscolins, in detail, through several analyses, including the CellKeyTM assay, cADDis® cAMP assay, and PathHunter® ß-arrestin recruitment assay, using cells stably expressing µ, δ, κ, or µ/δ heteromer opioid receptors. In the CellKeyTM assay, rubiscolins showed selective agonistic effects for δ opioid receptor and little agonistic or antagonistic effects for µ and κ opioid receptors. Furthermore, rubiscolins were found to be G-protein-biased δ opioid receptor agonists based on the results obtained in cADDis® cAMP and PathHunter® ß-arrestin recruitment assays. Finally, we found, for the first time, that they are also partially agonistic for the µ/δ dimers. In conclusion, rubiscolins could serve as attractive seeds, as δ opioid receptor-specific agonists, for the development of novel opioid analgesics with reduced side effects.
Assuntos
Peptídeos Opioides/farmacologia , Receptores Opioides delta/agonistas , Transdução de Sinais/efeitos dos fármacos , Spinacia oleracea/química , Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Estrutura Molecular , Peptídeos Opioides/química , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Receptores Opioides mu/metabolismo , Ribulose-Bifosfato Carboxilase/química , Ribulose-Bifosfato Carboxilase/farmacologia , beta-Arrestinas/metabolismoRESUMO
BACKGROUND: The misuse of opioids has led to an epidemic in recent times. The endothelin A receptor (ETAR) has recently attracted attention as a novel therapeutic target to enhance opioid analgesia. We hypothesized that endothelin A receptors may affect pain mechanisms by heterodimerization with µ opioid receptors. We examined the mechanisms of ETAR-mediated pain and the potential therapeutic effects of an ETAR antagonist, Compound-E, as an agent for analgesia. METHODS: Real-time in vitro effect of Compound-E on morphine response was assessed in HEK293 cells expressing both endothelin A and µ opioid receptors through CellKey™ and cADDis cAMP assays. Endothelin A/µ opioid receptor dimerization was assessed by immunoprecipitation and live cell imaging. The in vivo effect of Compound-E was evaluated using a morphine analgesia mouse model that observed escape response behavior, body temperature, and locomotor activity. RESULTS: In CellKey™ and cAMP assays, pretreatment of cells with endothelin-1 attenuated morphine-induced responses. These responses were improved by Compound-E, but not by BQ-123 nor by bosentan, an ETAR and endothelin B receptor antagonist. Dimerization of ETARs and µ opioid receptors was confirmed by Western blot and total internal reflection fluorescence microscopy in live cells. In vivo, Compound-E potentiated and prolonged the analgesic effects of morphine, enhanced hypothermia, and increased locomotor activity compared to morphine alone. CONCLUSION: The results suggest that attenuation by endothelin-1 of morphine analgesia may be caused by dimerization of Endothelin A/µ opioid receptors. The novel ETAR antagonist Compound-E could be an effective adjunct to reduce opioid use.
Assuntos
Analgésicos Opioides/administração & dosagem , Antagonistas do Receptor de Endotelina A/administração & dosagem , Morfina/administração & dosagem , Multimerização Proteica/fisiologia , Receptor de Endotelina A/metabolismo , Receptores Opioides mu/metabolismo , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Peptídeos Cíclicos/administração & dosagem , Multimerização Proteica/efeitos dos fármacosRESUMO
Opioid agonists elicit their analgesic action mainly via µ opioid receptors; however, their use is limited because of adverse events including constipation and respiratory depression. It has been shown that analgesic action is transduced by the G protein-mediated pathway whereas adverse events are by the ß-arrestin-mediated pathway through µ opioid receptor signaling. The first new-generation opioid TRV130, which preferentially activates G protein- but not ß-arrestin-mediated signal, was constructed and developed to reduce adverse events. TRV130 and other G protein-biased compounds tend to elicit desirable analgesic action with less adverse effects. In clinical trials, the intravenous TRV130 (oliceridine) was evaluated in Phase I, II and III clinical studies. Here we review the discovery and synthesis of TRV130, its main action as a novel analgesic having less adverse events, its up-to-date status in clinical trials, and additional concerns about TRV130 as demonstrated in the literature.