類鴉片mu和kappa受體調控痛覺與癢覺的行為神經機制

Abstract

在臨床上，許多疾病或藥物的使用會讓病患產生癢覺，而癢覺症狀的產生讓病患的日常生活品質下降，令人苦惱不已。因此，研究能夠抑制癢覺症狀的新藥物，是目前迫切需要的。臨床的研究發現，脊髓腔內注射類鴉片mu受體致效劑同時產生止痛與引發癢覺的功能。動物實驗也證明中樞給予類鴉片mu受體致效劑能引發搔癢的行為反應，而類鴉片kappa受體致效劑則可以降低類鴉片mu受體致效劑所引發的搔癢反應而不會干擾其止痛效果。本研究的目的，在於檢視類鴉片mu和kappa受體對於大白鼠的痛覺與癢覺的調控能力。藉由建立bombesin引發搔癢反應的動物行為模式，用以檢測實驗性藥物其抑制癢覺反應的功效，來比較類鴉片kappa受體致效劑、類鴉片mu受體拮抗劑以及組織胺受體拮抗劑對於bombesin所引發之搔癢反應的抑制效果。此外，並測試各類藥物在其引發癢覺或抑制癢覺時是否改變痛覺閾閥。最後，再透過側腦室給予類鴉片kappa受體拮抗劑來確認中樞神經系統裡類鴉片kappa受體在抗搔癢行為上的角色。研究結果得知兩項主要結論：（一）大白鼠的中樞類鴉片mu受體雖能抑制痛覺，但對於癢覺的傳遞或引發搔癢反應的功能有限。（二）不同類型的類鴉片kappa受體致效劑在無法抑制痛覺的低劑量範圍裡，都有抑制搔癢反應的效果。而且拮抗劑的使用，確認了中樞類鴉片kappa受體在抑制癢覺功能上的角色。相對於類鴉片mu受體拮抗劑及組織胺受體拮抗劑兩者都無法減緩bombesin所引發的搔癢反應，類鴉片kappa受體致效劑具有抑制不同根源的癢覺症狀的廣泛性。這些動物研究的發現有待進一步的臨床研究來確認類鴉片kappa受體致效劑作為新一代止癢藥物的潛在療效。

Itch/pruritus is a symptom derived from several diseases or drug use that afflicts a large population of humans. It is important to study and develop novel drugs as antipruritics. Clinical studies have shown that intrathecal administration of mu opioid receptor agonists simultaneously produces analgesia and itch. Animal studies have also shown that centrally administered mu opioids can elicit itch/scratching responses and that kappa opioid receptor agonists can attenuate intrathecal morphine-induced scratching without interfering with antinociception. The aim of this study was to investigate the roles of mu and kappa opioid receptors in modulating pain and itch sensation in rats. Experiments were conducted to establish bombesin-induced scratching as an itch model to evaluate the antiscratching effectiveness of various drugs. A thermal nociceptive assay was used to examine whether drugs eliciting or inhibiting scratching can change rat’s nociceptive threshold. In addition, antagonist experiments were conducted to verify the receptor mechanism underlying the antiscratching effects of kappa opioids. Findings from a series of experiments suggest that central mu opioid receptors in rats have limited functions in expressing scratching responses. More importantly, kappa opioid receptor agonists, but not an opioid receptor antagonist or a histamine receptor antagonist, can attenuate bombesin-induced scratching. The antiscratching effects of kappa opioids occur at low and non-antinociceptive doses and such effects can be reversed by a kappa opioid receptor antagonist. These findings warrant additional clinical studies to document effectiveness of kappa opioid receptor agonists as antipruritics in a broader context.