大鼠初級體感覺皮質與前扣帶迴皮質在疼痛生理功能中所扮演角色的比較

Abstract

疼痛包括感覺區辨，情緒動機和認知評價三種成份，本研究利用多頻道記錄系統同時記錄初級體感覺皮質(SmI)和前扣帶迴皮質(ACC )神經元的活動，比較兩個區域的神經元在遭受傷害性刺激時的反應，以及在恐懼情緒中的神經元活動變化，來探討SmI和ACC在疼痛感覺中所扮演的角色。雷射熱刺激能夠迅速且立即的引起痛覺，這種刺激也引起大腦頂葉部分的誘發電位LEP1和LEP2，平均反應時間分別為67±3 ms與356±7 ms。雷射熱刺激能夠引起大多數(88%)的SmI神經元活動的變化，其反應有許多不同的型式，大部份的SmI神經元呈現興奮性的反應，具有short-latency response (A+C0)或long-latency response (A0C+)或者兩者兼具(A+C+)，少數的神經元呈抑制性的反應；相對的，ACC對於雷射熱刺激只有51%的神經元有動作電位的反應。ACC神經元的反應除了前述四種型式外，還有一種持續性的晚期反應(long-lasting late response)。以神經元總體活動(ensemble unit activity)的角度來看，SmI和ACC神經元都具有short-latency response和long-latency response，SmI的平均反應時間分別為52±5 ms和368±9 ms，ACC的平均反應時間比SmI稍慢，分別為95±11 ms和395±23 ms； SmI對於雷射熱刺激的神經元反應比ACC反應的程度大。SmI和ACC的神經元反應均隨著刺激強度增加而提高，經過統計分析發現SmI的short-latency response對於因為雷射熱刺激強度增加而提高的反應明顯的高於ACC的short-latency response，顯示SmI的short-latency response對於反應刺激強度變化的coding能力優於ACC。 Morphine是臨床上常用的止痛劑，也具有很有效的鎮靜效果。本研究中測試全身性morphine的作用對於雷射熱刺激所引起的SmI和ACC反應的影響。在單一神經元的反應方面，結果顯示morphine對於ACC神經元有比較強的抑制作用；在總體神經元反應方面，morphine有效的降低SmI的long-latency response，對於short-latency response的影響則不是很明顯，但是，morphine對於ACC的short-latency response和long-latency response反應都有明顯的抑制；這部份的實驗利用藥理學的方法區分了SmI和ACC對痛覺刺激的不同的反應，其結果提供了證據顯示SmI 和ACC在痛覺處理上可能扮演不同的角色。 第三部分利用一個恐懼情緒的實驗設計，比較SmI和ACC神經元在大鼠學習恐懼情緒中的變化，在經過光亮訊息(CS)與足部電擊(US)的成功配對訓練之後，分別有60%及52%的ACC或SmI神經元對於CS的出現產生動作電位放電頻率的變化。神經元反應有三種不同的型式：sustained-excitatory、transient-excitatory以及inhibitory。其中表現sustained excitatory反應的ACC神經元，其反應的程度與驚跳反應的大小有關；而SmI神經元的反應程度則與驚跳反應的大小沒有顯著的關聯。 綜合以上的實驗結果，SmI比較能夠反應疼痛刺激的強弱，ACC則是在疼痛所引起的恐懼反應中扮演比較重要的角色；由此推論SmI主要負責疼痛的感覺區辨功能，而ACC較與疼痛的情緒動機功能有關。

It is recognized that there are three components in pain, namely, sensory-discriminative, affective-motivative and cognitive-evaluative. In this study, multi-site, multi single-unit recording technique was used to simultaneously record the neuronal activities in SmI and ACC in conscious, behaving rats. The roles of SmI and ACC in pain function were investigated by comparing the responses of neuronal activities in both areas to noxious laser-heat stimulation and neuronal activity changes in fear-potentiated startle paradigm. Laser-irradiation induced a rapid, immediate pain sensation. The laser evoked potentials (LEP1 and LEP2) were recorded simultaneously from a electrode in the skull. The latencies of LEP1 and LEP2 were 67±3 ms and 356±7 ms, corresponding to previous reports. SmI units (88%) were more responsive to laser heat than ACC units (51%). Most of these responsive units were either excitatory with short-latency response (A+C0) or long-latency response (A0C+) or a combinatory response (A+C+) and there were also units inhibited by laser heat. In addition to these four patterns of responses, some ACC units had a late, long-lasting response. The ensemble responses of SmI and ACC units had two peaks. The average latencies of short-latency response and long-latency response in SmI were 52±5 ms and 368±9 ms, respectively. The average latencies of ACC neuronal response were longer, 95±11 ms and 395±23 ms, respectively. The evoked ensemble responses in SmI was stronger than in ACC. Evoked responses in SmI and ACC grew stronger with increasing intensities of stimulation. Comparing the intensity dependent change, SmI had significantly higher correlation with tail-flick ratio of the rat than that in the ACC. Indicating a better encoding ability of the SmI of the stimulation intensity than ACC. The second part of this research examined the effect of morphine on the noxious laser-heat evoked responses of SmI and ACC. Systematic administration of morphine had stronger inhibition on ACC than SmI responses. The long-latency response of SmI ensemble unit activity was reduced significantly by 5 and 10 mg/kg of morphine. However, the same dosages had no effect on SmI short-latency response. In ACC, both short-latency response and long-latency response were inhibited significantly. The third part of the research compared the response of ACC and SMI in the fear potentiated startle paradigm, in which the rat learned to associate foot-shock (US) with a visual cue (CS). The rats jumped stronger with a sudden loud noise when the noise was paired with the CS light cue. Before conditioning, there was no neuronal change in neither light-noise trials (LNT) nor noise-only trials (NT). After conditioning, 60% ACC and 52% SmI units changed their firing rates in CS presenting period of LNT. Three patterns of neuronal changes were identified, i.e., sustained-excitatory, transient-excitatory and inhibitory. On average, the changes of ACC units were stronger than SmI units. Furthermore, the amount of change of sustained-excitatory units in ACC correlated positively to the strength of startle. In comparison, there was no significant correlation between neuronal change and startle strength in SmI units. To summarize, SmI could encode the intensity of noxious heat stimulation better than ACC. ACC activity correlated better to emotional response than SmI in fear-potentiated startle paradigm. In addition, ACC noxious response was more sensitive to morphine treatment. These results suggest that SmI is more important in sensory discriminating function and ACC is more important in emotional function of pain.