6 absence of inﬂammation. These results have clearly shown that ERK1/2 activation in the amygdala plays a pivotal role in inﬂammation-induced mechanical hypersensitivity. ERK1/2 activation mediates plasticity in various brain regions. ERK1/2 activation in the CeLC neuron also con- tributes to synaptic facilitation by increasing NMDA receptor function after peripheral inﬂammation [72]. Furthermore, it has been demonstrated that ERK1/2 activation in the CeLC is downstream of metabotropic glutamate receptor 5 (mGluR5) [73]. The level of mGluR5 in the right amygdala was higher than that in the left amygdala. This seems to be one of the mechanisms for hemispheric lateralization of pain processing in the amygdala. About the stress-induced activation of MAPKs, forced swim stress activated JNK, but not ERK1/2 and p38 MAPK, in the amygdala [74, 75]. The JNK signaling pathway is a major regulator for activation and expression of the AP-1 transcriptional factors such as c-Jun, c-Fos, and ATF. The activation of JNK may participate in stress-induced plastic change of the amygdaloid neurons. Maternal deprivation in early life increased immobility time in forced swim test and activation of ERK1/2 in the amygdala. Microinjection of PD98059 into the amygdala suppressed the immobility time. Thus, ERK1/2 activation in the amygdala seems to be implicated in the formation of depressive-like behavior [76]. 2.5. Cerebral Cortex. The cerebral cortices including the anterior cingulate (ACC) and prefrontal cortices (PFCs) are believed to play important roles in emotion, learning, memory, and persistent pain in the adult brain [77–79]. The electrical stimulation of the ACC produces facilitation of tail-ﬂick reﬂex induced by noxious heating via the RVM [80]. Formalin injection into the hindpaw activated ERK1/2 in rostral ACC (rACC) bilaterally [22]. A signiﬁcant increase of ERK1/2 activation in the rACC occurred at 3 min, peaked at 10–30 min, and declined at 2 h but still remained after 24 h. Inhibition of ERK1/2 activation in the rACC by microinjection of PD98059 did not aﬀect formalin-induced nociceptive behavior. However, PD98059 inhibited acquisition of formalin-induced conditioned place avoidance (F-CPA), which is believed to reﬂect pain-related negative emotion. ERK1/2 activation in the rACC required NMDA receptor, and it mediated CREB phosphorylation. However, the target genes regulated by CREB in the rACC remain to be elucidated. The activation of MAPKs including ERK1/2, JNK, and p38 MAPK has been shown to be critical for induction of LTP in the ACC [81]. The results have demonstrated that ERK1/2 activation in the rACC is critical for the development of aﬀective pain (pain-related emotional response) but not nociceptive pain [22]. Peripheral nerve injury, such as digit amputation, also activated ERK1/2 in the ACC at 2 weeks after amputation [23]. Nonnoxious mechanical stimulation by brushing the hindpaw with amputated digit increased further the number of p-ERK1/2 neurons in the ACC and p-ERK1/2 in the dendrite and synaptic sites. The activation of ERK1/2 at the synaptic sites is thought to be involved in rapid synaptic potentiation and regulation of neuronal excitability [81, 82]. Journal of Signal Transduction Acute stress such as restraint and forced swim activates ERK1/2 and JNK in the PFC and cingulate cortex [74, 83]. On the other hand, the eﬀects of chronic stress on MAPKs activation in the PFC are inconsistent across the previous studies. Chronic restraint and forced swim stresses decreased ERK1/2, JNK, and p38 MAPK activations in the PFC [83–85]. In contrast, chronic stress induced by inescapable footshock increased ERK1/2 activation in the PFC [86, 87]. What is the functional role of stress- induced alteration of MAPK activity in the PFC? Single- prolonged stress (SPS) consists of restrain for 2 h, forced swim for 20 min and ether anesthesia, and exposure to SPS activated ERK1/2 in the mPFC. Inhibition of ERK1/2 activation in the mPFC ameliorated stress-induced anxiety- like behavior, learning, and spatial memory impairment [88]. Antidepressant reversed stress-induced reduction of ERK1/2 activation in the PFC [85]. ERK1/2 activity in the PFC may be critical to depressive-like behavior and memory impairment. The rats subjected to prenatal stress showed a decrease of p38 MAPK activation in the PFC [89]. In these stressed rats, protein phosphatase-2A that dephosphorylates all MAPKs has been found to increase in the PFC. It has also been reported that p38 MAPK activation is involved in LTD at excitatory synapses of PFC pyramidal neurons [90]. These stress-induced reductions of MAPKs activation may impair synaptic plasticity. On the other hand, since sustained activation of MAPK induces neuronal degeneration [52], it is speculated that chronic stress-induced ERK1/2 activation may cause neuronal atrophy and reorganization [86, 87]. 2.6. Hypothalamus. Electrical stimulation or opioid microinjection in the hypothalamus produces analgesia, which has been considered to play an important role in the modulation of pain. Beta-endorphin neurons in the hypothalamic arcuate nucleus (Arc) project to the PAG and activate descending projection neurons to the RVM in the PAG by inhibiting inhibitory GABA-ergic interneurons. This neural circuit has been implicated in the production of stimulation-produced and stress-induced analgesia [1, 2, 91]. Formalin injection into the hindpaw activated ERK1/2 in the hypothalamus [24]. ERK1/2 activation markedly increased at 30 min and remained higher than baseline after 24 h. p-ERK1/2 was colocalized with beta-endorphin in the Arc neurons. Proopiomelanocortin (POMC) is a precursor to several active peptides, including beta-endorphin. The i.c.v. injection of PD98059 attenuated formalin-induced increase of POMC mRNA expression in the hypothalamus. These results indicate that ERK1/2 activation in the hypothalamus may contribute to neuroendocrine regulation [24]. ERK1/2 activation in the hypothalamic paraventricular nucleus (PVN) has also been reported after intraplantar formalin or i.t. SP injections [25, 26]. The i.c.v. injection of PD98059 attenuated the second phase of formalin-induced nociceptive behavior [26]. Therefore, ERK1/2 activation in the PVN may be involved in acute nociceptive behavior. Acute restraint stress activated ERK1/2 in the Arc and the PVN [60, 92]. Acute swim stress also activates JNK in the hypothalamus [75]. However, chronic restraint stress did