臨床上止癢藥物的發展有限,故尋找具有廣泛止癢效果的藥物及探討癢覺傳遞的 神經受體機制是相當重要的。從過去研究中發現,bombesin 能在嚙齒類動物引發強 烈的搔抓行為。另外,bombesin 對 bombesin receptor family 中的 gastrin- releasing peptide receptor(GRPr)和 neuromedin B receptor(NMBr)也有高度親 和力。本研究主要目的為釐清 GRPr 和 NMBr 是否具有獨立調控癢覺搔抓行為的能 力。藉由側腦室於大白鼠中樞給藥並量化大白鼠的後肢搔抓行為,建立 GRP 與 NMB 這兩種胜肽在大白鼠上引發搔抓行為的基本藥理特性,並透過 GRPr 與 NMBr 這兩種受體的專一性拮抗劑探討受體間對於調控癢覺搔抓行為的獨立性。透過每天連 續施打 bombesin、GRP 與 NMB 這三種胜肽探討大白鼠搔抓行為的耐受性及三種胜 肽引發之搔抓行為在長時間觀測上的比較。最後,利用 GRPr 與 NMBr 這兩種受體 的專一性拮抗劑來探討 bombesin 引發搔抓行為的機制。利用側腦室給予 GRP (0.03 - 0.3 nmol)與 NMB(0.1-1 nmol)皆引發劑量相關性的搔抓行為反應。GRPr 的拮抗劑 RC-3095 (0.1-1 nmol)可以劑量相關性地阻斷 GRP 所引發的搔抓行 為,但不能阻斷 NMB 所引發的搔抓行為。相對而言,NMBr 的拮抗劑 PD168368 (0.3-3 nmol)可以劑量相關性地阻斷 NMB 引發的搔抓行為,但不能阻斷 GRP 所引 發的搔抓行為。藉由這些拮抗劑實驗,証實了 GRPr 與 NMBr 兩受體皆調控癢覺的訊 息傳遞並獨立不互相影響。Bombesin、GRP 與 NMB 都能引發搔抓行為,但程度與 持續時間上都有差異。但是每天施打這三種胜肽皆引發搔抓行為的耐受性。然而, RC-3095 與 PD168368 的有效劑量或兩個拮抗劑的組合並不能阻斷 bombesin 所引 發的搔抓行為,意指 bombesin 所引發的搔抓行為可能由其他受體調控。由本研究得 知,GRPr 與 NMBr 分別獨立調控中樞神經系統的癢覺訊息傳遞,並有程度與持續時 間上的差異。更重要的是,綜合先前文獻研究讓我們瞭解 bombesin-recognized neurons 中還有其他重要的受體機制調控於中樞神經系統的癢覺傳遞。 / Bombesin is a pruritogenic agent that causes intense itch-scratching activity in rodents. Bombesin has high affinity for the gastrin-releasing peptide receptor (GRPr) and the neuromedin B receptor (NMBr). The aim of this study was to investigate pharmacologically the ability of GRPr and NMBr to themselves elicit scratching behavior in rats. The intracerebroventricular (i.c.v.) route was selected for drug delivery because the study focused on supraspinal sites of action. The magnitude and duration of scratching produced by the naturally occurring peptides GRP and NMB were characterized. Antagonists selective for GRPr (RC-3095) and NMBr (PD168368) were used to define the role of GRPr and NMBr in the scratching response. After i.c.v. administration, GRP (0.03-0.3 nmol) and NMB (0.1-1 nmol) dose-dependently elicited marked scratching. There was a tolerance to scratching elicited by daily repeated administration of bombesin, GRP, or NMB. Presession administration of RC-3095 (0.1-1 nmol) and PD168368 (0.3-3 nmol) dose- dependently antagonized scratching elicited by GRP and NMB, respectively. More important, 1 nmol of RC-3095 failed to block NMB- elicited scratching and 3 nmol of PD168368 failed to block GRP-elicited scratching. In addition, pretreatment with effective doses of RC-3095 or PD168368 alone or in combination did not block bombesin-elicited scratching. Through the use of the selective antagonists RC-3095 and PD168368, this study demonstrates that central GRPr and NMBr may act independently to elicit scratching behavior. Although the receptor mechanisms underlying bombesin-elicited scratching elude us, this study provides a pharmacological basis for GRPr and NMBr antagonists as potential antipruritics.

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.