前腦室側室丘對機械性痛敏感症的重要性

Abstract

中樞神經敏感化（central sensitization）對於發炎性（inflammatory pain），神經病理性（neuropathic pain）及慢性廣泛性疼痛（chronic widespread pain）所誘發之機械性痛敏感症（mechanical hyperalgesia）具有重要的生理調節的意義，然而在腦部這個層次中，我們認知的中樞神經敏感化對重要的痛覺調控功能之瞭解極是滄渺。學者們在神經電生理的研究指出，發炎性及神經病理性庝痛，會誘發由亞臂核（parabrachial area）到杏仁核中間核區（central nucleus of amygdala）突觸傳導增加的現象；加上在動物行為及生理的研究中，在承受以福馬林測試誘發發炎性庝痛的小鼠身上，也發現了改變杏仁核中間核區的胞外信號調節激素(ERK)的生理活性，能調控機械性痛敏症之增緩。 我們進期的研究更指出，受到酸刺激引發慢性肌肉痛的小鼠的杏仁核中間核區及前腦室側視丘（anterior nucleus of paraventricular thalamus，PVA）中之胞外信號調節激素會大量的活化，抑止在前腦室側視丘之胞外信號調節激素的活化反應，可進而絶斷慢性痛敏感性的發展。因此，我們提出調節胞外信號調節激素在前腦室側視丘的活性可以調控眾誘因造成之機械性痛敏感症之假說。 我們採用福馬林測試（formalin test）及坐骨神經分支選擇結紮切斷模式（spared nerve injury model, SNI）二種痛覺模式。首先，我們檢測以不同小鼠痛覺模式誘發機械性疼痛的小鼠的前腦室側視丘之調節胞外信號調節激素的活性；進而，我們鑑定胞外信號調節激素和機械性痛敏感症的依從性。研究的結果指出，前腦室側視丘中的磷酸化胞外信號調節激素在痛覺模式的小鼠身上劇增，以藥理調控此激素在該腦區的活性可進而舒緩或加劇機械性痛敏感症。最後，在無痛老鼠的前腦室側視丘中，直接以藥理活化胞外信號調節激素可誘發機械性痛敏感症，重複投藥更是造成小鼠發展出慢性機械性疼敏症。這些結果，再再指出PVA在痛覺調控的腦內機轉中扮演重要的生理調控功能。我們期待這些發現，除了能對腦部的痛覺生理調控機轉之基礎研究帶來新的思路，更希望有朝能在臨床上為相關疾患之有效療癒帶來新的轉機與曙光。

Central sensitization is important for development and maintenance of mechanical hyperalgesia in inflammatory, neuropathic and chronic widespread pain. The supraspinal mechanism for central sensitization is not completely understood in most pain models. Enhanced pain-related synaptic transmission from parabrachial area (PB) to central nucleus of amygdala (CeA) has been demonstrated in inflammatory and neuropathic pain. It has been shown that manipulation of ERK activity in CeA can alter the mechanical hyperlagesia induced by formalin in mice. We have recently shown that acid-induced chronic mechanical hyperalgesia also induced ERK activation in CeA and in the anterior nucleus of paraventricular thalamus (PVA) in mice. Blocking ERK activity in PVA blunts the chronic mechanical hyperalgesia. We therefore hypothesize ERK activation in PVA contributes to mechanical hyperalgesia in different pain models. To test this hypothesis, we examined the ERK activity in PVA in formalin-induced inflammatory pain and spared nerve injury (SNI)-induced neuropathic pain models and determined the association between ERK activation and mechanical hyperalgesia in female C57B6 mice. Our results showed that pERK staining in PVA were enhanced in both formalin- and SNI- induced mechanical hyperalgesia compared to their control. Manipulation ERK activity in PVA alters formalin-induced, SNI-induced and acid-induced persistent mechanical hyperaglesia. The direct infusion of PDBu in PVA induced mechanical but not thermal hyperaglesia in naive mice further pointed out the importance of PVA in nocicpetion transmission in brain circuit. Finally, the repeated infusion of PDBu in PVA induced the persistent mechanical hyperalgia strongly support that ERK activation in PVA plays a crucial role in modulation of mechanical hyperalgesia. The discovery of the importance of PVA in the central mechanism of nociceptive sensation is attributable not only to the basic understanding of pain perception but also to patients who are suffered from pain issues.