ACC HP T AMY AMY Acute forced swim p-JNK Maternal deprivation p-ERK1/2 Depressive-like behavior ACC Acute restraint p-ERK1/2 PAG LC RVM RVM Chronic restraint p-ERK1/2 PFC Acute restraint/forced swim p-ERK1/2, p-JNK Chronic restraint/forced swim p-ERK1/2, p-JNK, p-p38 MAPK Chronic footshock p-ERK1/2 Restrain + forced swim + ether p-ERK1/2 Depressive-like behavior learning and memory PFC HPT Acute restraint/forced swim p-ERK1/2, p-JNK LC Acute restraint p-ERK1/2 Chronic restraint p-ERK1/2 p-JNK p-p38 MAPK DLF SDH PAF Journal of Signal Transduction 5 Hindpaw plantar surface Figure 3: Schematic drawing of stress-induced MAPKs activations in the descending pain modulatory system. Boxes indicate psychophysical stress, activated MAPK, and function that is related to MAPK activation. For abbreviations see Figure 2. neurons that project to the RVM [67]. Many p-ERK1/2 neurons were found in the lateral, ventrolateral, and dorsal columns. However, the densities of p-ERK1/2 neurons in these columns were not signiﬁcantly diﬀerent [20]. These results indicate that ERK1/2 is activated in several PAG neurons related to the diﬀerent functional activity such as fear, anxiety, defensive reactions, and autonomic regulation in response to nociceptive stimuli. 2.4. Amygdala. The amygdala is now recognized as an important player in the emotional-aﬀective dimension of pain [68, 69]. It has also been demonstrated that this structure modulates nociceptive behavior by aﬀecting the activity of RVM [70, 71]. Peripheral inﬂammation activated ERK1/2 in the amygdala at 3 h after formalin injection into the hindpaw. Formalin-induced p-ERK1/2 neurons were almost exclusively located in the laterocapsular division of the central nucleus of the amygdala (CeLC) [21]. It is noteworthy that ERK1/2 activation was seen in the right CeLC, independent of the side of peripheral inﬂamma- tion. Inhibition of ERK1/2 activation in the amygdala by U0126 signiﬁcantly decreased mechanical but not thermal hypersensitivity. Pharmacological activation of ERK1/2 in the amygdala induced mechanical hypersensitivity in the