2 downstream components of MAPKs cascades (MAPKKKs). MAPKKKs activate MAPKKs, which are dual-speciﬁc kinases that phosphorylate at both Ser/Thr and Tyr sites, targeting a Thr-X-Tyr motif on the MAPKs (where X is glutamate (ERK1/2, ERK5), proline (JNK), or glycine (p38 MAPK)). The MAPKs, serine/threonine kinases, are activated by MAPKKs. Phosphorylation of the MAPKs results in a conformational change and a > 1000-fold increase in speciﬁc activity [10–12]. At the end of these signaling pathways, active MAPKs phosphorylate their target molecules, many of which are transcription factors, leading to facilitation of target gene expression. Thus, it is well established that neural MAPKs cascades play important roles in synaptic plasticity and remodeling during induction of long-term potentiation (LTP), learning, and memory consolidation [13, 14]. In the last 10 years, a number of studies have demon- strated that acute noxious stimuli, peripheral inﬂammation, and nerve injury activate MAPKs in several brain regions that are components of descending pain modulatory system [15–26]. These MAPKs activations play an important role in induction and maintenance of neural plasticity, which is thought to be essential for understanding the mechanism underlying dynamic changes in descending pain modulatory systems following peripheral tissue injury [5–7, 27]. To explore the role of each MAPK signaling pathway, the speciﬁc inhibitors such as ERK1/2 inhibitor (MEK inhibitor PD98059, U0126), p38 MAPK inhibitor (SB203580), and JNK inhibitor (SP600125) have been used in these studies [28]. The administrations of these inhibitors to descending pain modulatory systems alleviated hyperalgesia and allody- nia in peripheral inﬂammatory pain models. [18, 21, 29]. In this paper, ﬁrst, we introduce which MAPK is activated by such noxious stimuli and where those activations occur in descending pain modulatory system. Pain is a complex experience that involves not only the transduction of noxious environmental stimuli, but also cognitive and emotional processing in the brain [30]. Second, we discuss which of pain perception, pain-related emotional responses, and pain-related memory is the activation of MAPKs in these components related with it. Stress aﬀects brain activity and promotes long-term changes in multiple neural systems. A variety of environmen- tal and/or stressful stimuli have been shown to induce not only pain suppression but also an increase in pain sensitiv- ity. These phenomena are termed stress-induced analgesia (SIA) and stress-induced hyperalgesia (SIH), respectively [31]. Stress has also been found to exacerbate and could contribute to the etiology of chronic painful disorders, such as, ﬁbromyalgia [32], irritable bowel syndrome [33], rheumatoid arthritis [34], and headache [35]. Psychophysical stress also activates MAPKs in brain structures related to descending pain modulatory system. MAPKs-induced neural plasticity in some of these structures might be associated with “limbically augmented pain syndrome” [36]. In this theory, stress and emotionally traumatic events lead to a sen- sitization of corticolimbic structures, which subserve both nociceptive processing and aﬀective regulation. Therefore, we also discuss stress-induced activations of MAPKs in these structures. Journal of Signal Transduction 2. Activation of Mitogen-Activated Protein Kinase in Descending Pain Modulatory System 2.1. Rostral Ventromedial Medulla (RVM). Peripheral in- ﬂammation induced by CFA injection into the hindpaw activated ERK1/2 and p38 MAPK in the RVM. The activation of ERK1/2 exhibited two characteristic phases. The ﬁrst phase was a transient small increase at 30 minutes after CFA injection. The second phase was more persistent and pronounced increase from 3 hours to 24 hours, with a peak at 7 hours [15]. On the other hand, the activation of p38 MAPK was more short lived. It peaked at 30 minutes and lasted for 1 hour [16] (Figure 1). Phosphorylated ERK1/2 and p38 MAPK (p-ERK1/2 and p-p38 MAPK) were present predominantly in RVM neurons after CFA injection. About 60% of p-ERK1/2 neurons and 40% of p-p38 MAPK neurons in the RVM were serotonergic neurons [15, 16]. Microglial p-p38 MAPK in the RVM has also been reported to increase following carrageenan-induced inﬂammation [18]. Microinjection of U0126, an MEK inhibitor, into the RVM partially restored a decrease of paw withdrawal latency to noxious heat stimulus into the inﬂamed hindpaw [29]. ERK1/2 is involved in both transcription-independent and transcription-dependent forms of central sensitization. The former is early onset process, such as phosphorylation of receptors and traﬃcking of receptors to the synapse, and the latter is late onset, such as an increase in the expression of late-response genes [27, 37]. Since the microinjection of U0126 into the RVM signiﬁcantly attenuated thermal hyperalgesia at 24 hours, but not at 7 hours after CFA injection [29], activation of ERK1/2 in the RVM might be involved in transcription-dependent plasticity. It has been demonstrated that the phosphorylation of ERK1/2 activates the transcription of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, in the serotonergic neuron-like cell line [38]. Thus, activation of ERK1/2 in RVM serotonergic neurons is assumed to increase serotonin biosynthesis. 5-hydroxytryptamine (5HT) released from the descending bulbospinal neurons seems to exert dual (inhibitory and facilitatory) eﬀects on spinal nociceptive processing [2, 3]. Oyama et al. [39] reported that the inhibitory and facilitatory eﬀects were mediated by 5HT1A and 5HT3 receptors, respectively. Nearly one- half of DRG neurons projecting to the superﬁcial dorsal horn express 5HT3 receptor [40], and activation of 5HT3 receptor localized on central terminals of DRG neurons seems to enhance the release of neuropeptides [41]. Recently, by depleting endogenous 5HT in the RVM serotonergic neurons, it has been demonstrated that the RVM 5HT system participates in descending pain facilitation but not descending inhibition, which is necessary for maintenance of hyperalgesia and allodynia after peripheral inﬂammation and nerve injury [42]. Thus, it is possible that ERK activation induced by inﬂammation increases the transcription of TPH and serotonin biosynthesis, leading to the enhancement of hyperalgesia via descending serotonergic pathways. Microinjection of SB203580, a p38 MAPK inhibitor, into the RVM attenuated carrageenan-induced thermal