神經生物學的新發現與轉譯醫學的臨床應用在癢治療的新進展

Itch Therapy Progress from New Discovery of Basic Neurobiology to Clinical Applications of Translational Medicine

「癢」是一種保護感覺(protective sensation)，是對於致癢源(pruritogens)的搔抓反應。相對於「痛」，雖然一樣是保護感覺，但是兩者從周邊受體，一直到中樞的訊息傳遞、處理，除了有共同的機制(shared mechanisms)，也有特定的病態生理學(unique pathophysiology)，最典型的是：最終的反應不同，「癢」以搔抓表現，「痛」則以逃脫表現。這些神經生物學研究提供了藥物研發的基礎，這一綜說：（1）介紹癢最近10年研究的新進展；（2）比較與痛覺神經生物學的異同；（3）探討這些基礎神經科學資訊與轉譯硏究，對於臨床精準醫學的應用。在皮膚周邊組織，除了受體，還需要相關成分的交互作用，包括致癢源、皮膚微環境（微血管及血管內分子等）、細胞（表皮細胞、免疫細胞，比如樹狀細胞、T細胞、嗜鹼性球、肥大細胞(mast cell)等），以及特定的神經末梢，比痛覺刺激的周邊反應更為複雜。痛覺的刺激傳遞包括受體、背根神經節神經元、脊髓背角、脊髓上行路徑、視丘、大腦皮質。最終在大腦皮質約處理，包括：（1）區辨層次（在視丘與體感覺的皮質）；（2）情緒層次（邊緣系統）。因為癢是保護感覺，臨床評估約第一步是檢查癢是否有皮膚的病灶，如果沒有皮膚病灶，就要評估是否有全身性疾病(systemic disease)、神經的異當活化，或者心理與社會環境的交互作用所誘發與維持。在最近10年，因為特定癢覺受體的發現，即Mas相關的G蛋白鍵合受體(Mas related G protein-coupled receptor，簡稱MRGPR)，提供了新穎藥物研發的可能。而基於致癢機制，應用新的生物製劑，如阻斷介白素31 (interlenkin 31)等等，對於癢的治療，應用精準醫學的原則。綜上所述，最近10年以來，在癢的研究進展，從周邊受體到大腦中樞的可塑性變化，提供了止癢藥物的研發與精準醫學的應用。

Itch is a protective sensation with a scratching response to pruritogens, in contrast to pain, which shows an escaping phenomenon as the response element. Both itch and pain have shared mechanisms and unique pathophysiology in neural substrates from the level of peripheral receptors and the central processing spinal cord and brain, respectively. During the previous decade, there has been substantial progress in our understanding on the basic neurobiology of itch which provides foundations of developing new medications for itch. From neurobiology and circuitry points-of-view, itch is initiated from the peripheral receptors in the skin. They are localized at the nerve terminals of primary sensory neuron (first order neuron) in the dorsal root ganglia which interact with various cells in the epidermis and dermis of the skin including keratinocyte, immune cells, such as dendritic cell, T cell, eosinophil, and mast cell etc. The itch signals will then synapse with the second order neurons in the dorsal horn of the spinal cord, and then transmitted via spinothalamic tract to the thalamus. Such itch signals will be processed in the brain including: (1) discriminative perspective at the somatosensory cortex and (2) affective perspective at the limbic system. Over the last decade, the most important progress in the itch field is the discovery of Mas-related G protein-coupled receptor (MRGPR) which opens a new avenue for designing new therapeutic targets for itch. The assessment and treatment of chronic itch pose a challenge in clinical practice. The first step is to identify the cause of itch, in particular, structural lesions or systemic diseases, such as uremia. The next step is then to prescribe personized and specific theapies based on itch mechanisms and pathophysiology, including conventional antihistamine or biologics of new generation, such as the antagonist against interleukin 31 receptor. In summary, over the past ten years, we have seen the remarkable progress in itch neurobiology which offers a new horizon for designing new therapeutic strategies for chronic itch.