Nội dung được dịch bởi AI, chỉ mang tính chất tham khảo
Tầm quan trọng của các biến thể splice của thụ thể mu-opioid và tính linh hoạt của các hệ quả tín hiệu của chúng đối với sự tolérance thuốc giảm đau opioid
Tóm tắt
Việc tăng liều opioid để kiểm soát hiệu quả cơn đau thường gắn liền với đại dịch lạm dụng opioid hiện nay. Điều này tạo ra những yêu cầu xã hội cũng như y tế để hiểu rõ hơn về các cơ chế cơ bản của sự tolérance opioid nhằm phát triển các can thiệp làm giảm thiểu tình trạng này, qua đó tối đa hóa hiệu quả giảm đau của opioid. Sự tolérance giảm đau opioid sâu sắc có thể được quan sát thấy mà không có sự giảm điều hòa thụ thể mu-opioid (MOR), tích tụ G protein MOR không kết nối, và sự giảm nhạy cảm của MOR, không có sự suy yếu phosphorylation của kinase thụ thể kết nối protein G, kết dính arrestin, hoặc nội thực bào. Do đó, chúng tôi đã khám phá các hệ quả sinh hóa thay thế có thể giải thích tốt hơn cho sự tolérance giảm đau opioid. Các phát hiện của chúng tôi cho thấy tính dẻo dai đáng kể giữa các thành phần thượng nguồn và hạ nguồn của tín hiệu thụ thể opioid và sự xuất hiện của các con đường tín hiệu thay thế là những yếu tố chính góp phần vào sự tolérance giảm đau opioid. Một ví dụ về tính dẻo dai này là các phát hiện của chúng tôi cho thấy morphine mãn tính làm gia tăng các biến thể MOR MOR-1B2 và MOR-1C1 cũng như phosphorylation ở các vị trí tận cùng C của chúng không có trong MOR-1, những sự kiện có liên quan nguyên nhân với sự chuyển dịch kết nối G protein MOR từ chủ yếu ức chế Gi/Go sang kích thích Gs đối với tín hiệu adenylyl cyclase. Các đặc điểm độc đáo của những biến thể này liên quan đến sự dễ dàng thích ứng với morphine mãn tính bằng cách thay đổi tính chất của kết nối protein G cho thấy sự phong phú và tính linh hoạt của tín hiệu MOR được tạo điều kiện bởi sự phát sinh đa dạng rộng lớn của các biến thể MOR. Hơn nữa, với các mô hình biểu hiện giải phẫu khác nhau của các biến thể MOR, các điều chỉnh phụ thuộc vào biến thể splice của MOR đối với morphine mãn tính có thể cho phép làm sáng tỏ các cơ sở cơ chế của sự tolérance và phụ thuộc mà là đặc hiệu cho từng vùng CNS và từng tế bào.
Từ khóa
#thuốc giảm đau opioid #thụ thể mu-opioid #tolérance opioid #tín hiệu thụ thể #biến thể spliceTài liệu tham khảo
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