痛みによる不快情動生成の神経機構(シンポジウム:慢性疼痛の基礎と臨床,2008年,第49回日本心身医学会総会(札幌))  [in Japanese] Neuronal Mechanisms for Pain-induced Aversion(Symposium/The Mechanism and Practice of Chronic Pain)  [in Japanese]

痛みは,侵害刺激が加わった場所とその強さの認知にかかわる感覚的成分と侵害刺激受容に伴う不安,嫌悪,恐怖などの負の情動(以下,不快情動)の生起にかかわる情動的成分からなる.痛みによる不快情動生成における扁桃体の役割を検討したところ,体性痛に関する情報は基底外側核(BLA)を経て中心核(CeA)に入った後,一方,内臓痛に関する情報はBLAを介さずCeAに入った後,不快情動を生成する可能性が示された.この体性痛による不快情動生成には,BLA内グルタミン酸神経情報伝達が重要であること,モルヒネがこの情報伝達を抑制的に調節することも明らかにした.さらに,"extended amygdala"を構成する脳領域である分界条床核において,痛み刺激によりノルアドレナリン遊離が促進され,このノルアドレナリンによるβ受容体を介した神経情報伝達亢進もまた痛みによる不快情動生成に重要であることを明らかにした.

Background: Pain contains sensory discriminative and negative affective components. Although the neural systems responsible for the sensory component of pain have been studied extensively, the neural basis of the affective component is not well understood. We examined the neural circuits and mechanisms underlying the negative affective component of pain using a conditioned place paradigm. Methods: Male Sprague-Dawley rats were used for all experiments under the approval of the Institutional Animal Care and Use Committee. Pain-induced aversion was assessed by a conditioned place aversion (CPA) test. Glutamate and noradrenaline releases within the basolateral amygdaloid nucleus (BLA) and bed nucleus of the stria terminalis (BNST), respectively, were examined by using an in vivo microdialysis technique. Results: Excitotoxic lesions of the BLA abolished intraplantar formalin-induced CPA (F-CPA), but not intraperitoneal acetic acid-induced CPA (A-CPA). On the other hand, excitotoxic lesions of the central amygdaloid nucleus (CeA) abolished both F-CPA and A-CPA. These findings suggest that the BLA and CeA are differently involved in somatic and visceral pain-induced aversion. Next, we examined the role of glutamatergic transmission within the BLA in F-CPA. Microinjection of MK-801 into the bilateral BLA 5min. before intraplantar injection of formalin dose-dependently attenuated F-CPA without affecting nociceptive behaviors. On the contrary, microinjection of neither CNQX nor AP-3 showed any significant effect on F-CPA. In vivo microdialysis experiments revealed that intraplantar injection of formalin induced an increase in the extracellular glutamate level within the BLA. This increase in glutamate was suppressed by morphine perfusion via the microdialysis probe. Moreover, intra-BLA injection of morphine 5min before formalin injection attenuated F-CPA without affecting nociceptive behaviors. Finally, we examined the role of noradrenergic transmission within the BNST, especially the ventral part of the BNST (vBNST), in F-CPA. In vivo microdialysis showed that extracellular noradrenaline levels within the vBNST were significantly increased by intraplantar formalin injection. Using the CPA test, we found that intra-vBNST injection of timolol, a β-adrenoceptor antagonist, dose-dependently attenuated F-CPA without reducing nociceptive behaviors. Intra-vBNST injection of isoproterenol, a β-adrenoceptor agonist, dose-dependently produced CPA even in the absence of noxious stimulation. This isoproterenol-induced CPA was reversed by the co-injection of Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS), a selective PKA inhibitor. Furthermore, intra-vBNST injection of Rp-cAMPS dose-dependently attenuated the F-CPA. Conclusion: These results suggest that glutamatergic transmission via NMDA receptors within the BLA plays a crucial role in the pain-induced aversion, and that in addition to the well-characterized effects on the sensory component of pain, morphine also influences the affective component of pain through an inhibitory effect on intra-BLA glutamatergic transmission. Furthermore, it was demonstrated that PKA activation within the vBNST via the enhancement of β-adrenergic transmission is important for the pain-induced aversion.