TI - Inflammatory pain is associated with activation of ERK1/2 in cortical neurons . AB - What do these ex-vivo slice findings mean in the context of plasticity in the cortex in vivo? LTP in the ACC is proposed to be a key cellular model [30 , 36-38] and ACC LTP is likely contributing to both the early cortical changes in the ACC as well as plastic changes in the ACC after the injury [2] . We therefore chose mouse models of persistent nociceptive activity to address mechanisms of synaptic plasticity in the ACC in vivo . Recent work from our lab as well as others showed that ACC ERK is activated after peripheral inflammation [39,40] . Considering the fact that ERK activity is required for ACC LTP [14] , it is conceivable that activity -dependent LTP may contribute to activation of ERK1/2 in the ACC in animal models of persistent pain . To address the cortical levels of activated ( PHOSphorylated ) ERK1/2 in inflammatory pain states , we utilized mouse models based upon intraplantar injection of 1% formalin or complete Freund's adjuvant ( CFA ) in the mouse hindpaw . The plantar formalin test is a measure of rapid sensitization of nociceptive pathways and involves formalin-evoked nocifensive responses in two phases : an acute phase I ( 0-10 minutes following injection ) , which is caused by direct activation of nociceptors by formalin and a subacute phase II ( 15-50 minutes ) , which is believed to involve spinal , cortical as well as peripheral sensitization mechanisms . In the basal ( naive ) state , only a few neurons in the ACC showed immunoreactivity for PHOSphorylated ERK1/2 ( pERK1/2 ) (Fig 7A) . At 10 minutes after formalin injection , a significant increase was observed in the immunoreactivity for pERK over neurons of the ACC , as judged by densitometry ( P lt 005 as compared with basal levels ; see Fig 7A for typical examples and Fig 7B for quantitative summary ) . Whereas only a few neurons demonstrated strong immunoreactivity over the neuronal somata in the basal state , following formalin injection , prominent immunoreactivity was observed in the dendrites as well as the somata of a large number of neurons ( Fig 7A , higher magnification ) . Formalin-induced increase in pERK immunoreactivity was sustained at 30 minutes after injection , and returned to basal levels at 60 min after injection , after the phase II response had subsided ( Fig 7B ) . To address whether long-lasting hypersensitivity evoked by peripheral inflammation is associated with cortical activation of ERK1/2 , we analyzed pERK1/2 immunoreactivity at 10 min , 30 min and 3 hours after hindpaw injection of CFA . Injection of CFA in the hindpaw triggered inflammation within minutes and led to a rapid and long-lasting hyperalgesia to thermal and mechanical stimuli ( Fig 7B ) . Concurrent to the course of hyperalgesia , CFA evoked a rapid and long-lasting increase in pERK immunoreactivity over neurons of the ACC ( see Fig 7A and Fig 7B for summary ; P lt 005 as compared with basal levels ) . In particular , intense immunoreactivity was observed in the dendrites and neuropil after CFA administration ( Fig 7A , higher magnification ) .