4 Journal of Signal Transduction PFC HPT Formalin injection p-ERK1/2 POMC production Formalin-induced nociceptive behavior HPT PAG Acetic acid i.p. injection p-ERK1/2 DLF SDH LC Formalin injection p-ERK1/2 PAF ACC Formalin injection p-ERK1/2 Formalin-induced conditioned place avoidance ACC AMY LC RVM PAG RVM CFA injection p-ERK1/2 Thermal hyperalgesia Carrageenan injection p-p38 MAPK Thermal hyperalgesia mechanical allodynia AMY Formalin injection p-ERK1/2 Mechanical hypersensitivity Hindpaw plantar surface Figure 2: Schematic drawing of noxious stimuli-induced MAPKs activations in the descending pain modulatory system. Boxes indicate noxious stimulation, activated MAPK, and function that is related to MAPK activation. PFC, prefrontal cortex; ACC, anterior cingulate cortex; AMY, amygdala; HPT, hypothalamus; PAG, periaqueductal gray; LC, locus coeruleus; RVM, rostral ventromedial medulla; DLF, dorsolateral funiculus; SDH, spinal dorsal horn; PAF, primary aﬀerent ﬁber; POMC, proopiomelanocortin. Upward and downward arrowheads indicate increase and decrease, respectively. be due to the diﬀerences in duration of restraint stress and experimental protocol. Short-term anaesthesia has been shown to induce ERK1/2 phosphorylation in the brainstem [62]. LC neurons in waking animals are very responsive to nonnoxious auditory, visual, and somatosensory stimuli in the environment [63–66]. Thus, we must take careful note of anesthesia, handling of animals, and experimental environment to evaluate an activation of MAPK in the LC. 2.3. Periaqueductal Grey (PAG). There are few studies that investigate activation of MAPK in the PAG. Some studies have reported the activation of ERK1/2 in the PAG after visceral noxious stimulation [19, 20]. Intraperitoneal injec- tion of acetic acid signiﬁcantly activated ERK1/2 in the PAG [19, 20]. The PAG has a longitudinal columnar organization, and each PAG column coordinates a distinct pattern of behavioral and physiological reactions critical for survival. The lateral and ventrolateral cell columns contain many