類鴉片mu和kappa受體在調節痛覺與癢覺功能的行為神經機制

Abstract

在臨床上，許多疾病或藥物的使用會引發癢覺，但引發癢覺的藥理機制尚未被完全確認。最近研究發現兩種不同方式引發的癢覺是由不同的感覺神經細胞傳導，並且不同的受體參與傳達癢覺與痛覺的機制。因此，利用動物模式來探討受體在癢覺與痛覺上的關係有其必要性與價值。先前研究發現，中樞神經mu類鴉片受體的激發會產生止痛與搔癢行為，而kappa類鴉片受體致效劑則可抑制mu類鴉片受體所引發的癢覺而不會干擾其止痛的效果。此計畫欲運用藥理學方法，使用能引發癢覺的藥物來建立癢覺動物模式，並探討kappa類鴉片受體致效劑在不同的癢覺動物模式裡，其能抑制癢覺的潛在功能。本研究計劃假設激發kappa類鴉片受體能減緩因激發不同受體所引發的搔癢行為。由不同的動物模式(包含DAMGO及bombesin等所引發的搔癢反應)，透過藥理操弄而比較不同的藥物其降低搔癢行為的效果，並使用拮抗劑來確認kappa受體在抗搔癢行為上的角色。此外，測試痛覺的反應來檢驗動物的痛覺閾閥是否受到不同的藥物的影響。本研究將建立中樞引發癢覺之動物模式，並比較kappa受體致效劑與mu受體拮抗劑以及組織胺拮抗劑在抑制癢覺上的效果。本計劃將有助於在癢覺與痛覺的藥物研究，並提供kappa受體致效劑未來被應用在臨床上之可能性。

Itch sensation (Pruritus) is a symptom of many clinical disorders that afflicts a large population of humans and is treated by a variety of pharmacological agents with variable success. Little effort has been made to understand the basic mechanisms by which itch sensation is provoked. Recent studies illustrate distinct sensory neurons responding to two different pruritogenic agents and several receptor mechanisms regulating the itch or/and pain sensation. Therefore, it is important to conduct studies using behaving animals to investigate the receptor mechanisms modulating itch and pain sensation. In our previous studies, we have demonstrated that central mu opioid receptors mediate both antinociception and itch/scratching responses and that kappa opioid receptor agonists can inhibit mu opioid receptor agonist-elicited scratching responses without decreasing antinociception. Using pharmacological approaches, we intend to establish other experimental itch models with different pruritogenic agents and to determine the effectiveness of kappa opioid receptor agonists as antipruritics in a broader context in behaving animals. The proposed studies in this project will test the central hypothesis that activation of kappa opioid receptors attenuates itch evoked by a variety of pruritogenic agents in rodents. In the proposed studies, scratching activity will be monitored by video recorders and quantified by observers blind to experimental conditions. The potential attenuation of scratching activity by rationally selected pharmacological agents will be studied in different experimental itch models including i.c.v. DAMGO- and bombesin-induced scratching responses. In addition, hot plate nociceptive assay will be used to measure whether the rodent』s nociceptive threshold is changed when receiving different pharmacological agents alone or in combination. Antagonist studies will be conducted to verify the role of kappa opioid receptors in the anti-scratching effects of various kappa opioid receptor agonists. This proposal will further establish experimental models of centrally elicited itch and compare the effectiveness of kappa opioid receptors agonists, opioid receptor antagonists, and histamine receptor antagonists as antipruritics under these conditions. Theses studies will provide a substantial contribution to the in vivo pharmacology of itch and pain, and establish a translational basis for kappa opioid receptor agonists as potential antipruritics in humans.