Neuronal Mechanisms for Pain-induced Aversion(Symposium/The Mechanism and Practice of Chronic Pain)

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.