RESUMO
Prolonged use of opioids can cause opioid-induced hyperalgesia (OIH). The impact of alternative splicing on OIH remains partially characterized. A study of the absolute and relative modes of action of alternative splicing further the understanding of the molecular mechanisms underlying OIH. Differential absolute and relative isoform profiles were detected in the trigeminal ganglia and nucleus accumbens of mice presenting OIH behaviors elicited by chronic morphine administration relative to control mice. Genes that participate in glutamatergic synapse (e.g., Grip1, Grin1, Wnk3), myelin protein processes (e.g., Mbp, Mpz), and axon guidance presented absolute and relative splicing associated with OIH. Splicing of genes in the gonadotropin-releasing hormone receptor pathway was detected in the nucleus accumbens while splicing in the vascular endothelial growth factor, endogenous cannabinoid signaling, circadian clock system, and metabotropic glutamate receptor pathways was detected in the trigeminal ganglia. A notable finding was the prevalence of alternatively spliced transcription factors and regulators (e.g., Ciart, Ablim2, Pbx1, Arntl2) in the trigeminal ganglia. Insights into the nociceptive and antinociceptive modulatory action of Hnrnpk were gained. The results from our study highlight the impact of alternative splicing and transcriptional regulators on OIH and expose the need for isoform-level research to advance the understanding of morphine-associated hyperalgesia.
Assuntos
Processamento Alternativo/genética , Analgésicos Opioides/efeitos adversos , Hiperalgesia/genética , Morfina/efeitos adversos , Fatores de Transcrição ARNTL/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/patologia , Proteínas com Domínio LIM/genética , Masculino , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas do Tecido Nervoso/genética , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de N-Metil-D-Aspartato/genética , Proteínas Repressoras/genética , Transdução de Sinais/efeitos dos fármacos , Sinapses/genética , Gânglio Trigeminal/metabolismoRESUMO
OBJECTIVE: To test the hypotheses that emerging viruses are associated with neurological hospitalizations and that statistical models can be used to predict neurological sequelae from viral infections. METHODS: An ecological study was carried out to observe time trends in the number of hospitalizations with inflammatory polyneuropathy and Guillain-Barré syndrome (GBS) in the state of Rio de Janeiro from 1997 to 2017. Increases in GBS from month to month were assessed using a Farrington test. In addition, a cross-sectional study was conducted analyzing 50 adults hospitalized for inflammatory polyneuropathies from 2015 to 2017. The extent to which Zika virus symptoms explained GBS hospitalizations was evaluated using a calibration test. RESULTS: There were significant increases (Farrington test, P<0.001) in the incidence of GBS following the introduction of influenza A/H1N1 in 2009, dengue virus type 4 in 2013, and Zika virus in 2015. Of 50 patients hospitalized, 14 (28.0%) were diagnosed with arboviruses, 9 (18.0%) with other viruses, and the remainder with other causes of such neuropathies. Statistical models based on cases of emerging viruses accurately predicted neurological sequelae, such as GBS. CONCLUSION: The introduction of novel viruses increases the incidence of inflammatory neuropathies.