Hindawi Publishing Corporation Journal of Signal Transduction Volume 2011, Article ID 468061, 10 pages doi:10.1155/2011/468061 Review Article Activation of Mitogen-Activated Protein Kinase in Descending Pain Modulatory System Hiroki Imbe,1 Emiko Senba,2 Akihisa Kimura,1 Tomohiro Donishi,1 Isao Yokoi,1 and Yoshiki Kaneoke1 1 Department of Physiology, Wakayama Medical University, Kimiidera 811-1, Wakayama City 641-8509, Japan 2 Department of Anatomy and Neurobiology, Wakayama Medical University, Kimiidera 811-1, Wakayama City 641-8509, Japan Correspondence should be addressed to Hiroki Imbe, imbe@wakayama-med.ac.jp Received 8 August 2010; Accepted 14 October 2010 Academic Editor: Kohsuke Takeda Copyright © 2011 Hiroki Imbe et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The descending pain modulatory system is thought to undergo plastic changes following peripheral tissue injury and exerts bidirectional (facilitatory and inhibitory) inﬂuence on spinal nociceptive transmission. The mitogen-activated protein kinases (MAPKs) superfamily consists of four main members: the extracellular signal-regulated protein kinase1/2 (ERK1/2), the c-Jun N-terminal kinases (JNKs), the p38 MAPKs, and the ERK5. MAPKs not only regulate cell proliferation and survival but also play important roles in synaptic plasticity and memory formation. Recently, many studies have demonstrated that noxious stimuli activate MAPKs in several brain regions that are components of descending pain modulatory system. They are involved in pain perception and pain-related emotional responses. In addition, psychophysical stress also activates MAPKs in these brain structures. Greater appreciation of the convergence of mechanisms between noxious stimuli- and psychological stress-induced neuroplasticity is likely to lead to the identiﬁcation of novel targets for a variety of pain syndromes. 1. Introduction In human brain, there is a neural network that modulates the transmission of nociceptive messages, which is termed descending pain modulatory system. The cerebral cortex and amygdala project directly and indirectly via the hypothala- mus to the periaqueductal grey (PAG). The PAG in turn con- trols spinal nociceptive neurons through relays in the rostral ventromedial medulla (RVM) and the dorsolateral pontine tegmentum (DLPT). The RVM consists of the nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis pars alpha (GiA), and the ventral nucleus reticularis gigantocellu- laris (Gi) and is a major source of serotonergic projections to the spinal dorsal horn. The DLPT includes the noradrenergic neurons, such as the locus coeruleus (LC), A5 and A7, which are major sources of noradrenergic projections to the dorsal horn. These descending inputs especially from the RVM exert bidirectional (facilitatory and inhibitory) inﬂuence on nociceptive transmission in the spinal dorsal horn [1–3]. In earlier studies, attention has been mainly focused on the descending inhibitory inﬂuence. However, recently, it has also been known that the descending input from the RVM facilitates neuronal responses in the spinal dorsal horn and contributes to persistent pain and hyperalgesia [2–4]. Descending modulation is not a static process but exhibits dynamic changes in response to persistent noxious input following peripheral inﬂammation and nerve injury [5–7]. The mitogen-activated protein kinases (MAPKs) are a superfamily of intracellular signal transduction molecules that are evolutionally conserved [8, 9]. The MAPKs super- family is made up of four main and distinct signaling pathways: the extracellular signal-regulated protein kinase1/2 (ERK1/2), the c-Jun N-terminal kinases or stress-activated protein kinases (JNK/SAPKs), the p38 MAPKs, and the ERK5. Each of MAPKs signaling pathways involves a con- secutive activation of four levels of signaling molecules: small GTPases (Ras or Rac), MAPK kinase kinases (Raf or MAPKKKs), MAPK kinases (MEKs or MAPKKs), and MAPKs. The initial Ras and Rac localize to the inner surface of plasma membrane and transmit extracellular signals to