Glutamatergic transmission and plasticity in the brain are critical for behaviors, such as memory, addiction, and chronic pain. In the anterior cingulate cortex (ACC), a brain area related to persistent pain, peripheral inflammation caused functional alterations in NMDA receptors and glutamate release (Wu et al., 2005; Zhao et al., 2006). The mechanism underlying the regulation of glutamatergic transmission remains elucidated. Among many possible candidate molecules, cyclic AMP (cAMP) is a key second messenger for synaptic plasticity and chronic pain in the ACC. We have found impaired synaptic plasticity in the ACC (Liauw et al., 2005) and attenuated behavioral sensitization in various chronic pain models in mice lacking calmodulin-stimulated adenylyl cyclase (AC ) 1 and AC8 (Wei et al., 2002). Moreover, cAMP pathway is involved in both postsynaptic and presynaptic alterations in the ACC after chronic pain (Wu et al., 2005; Xu et al., 2008; Zhao et al., 2006). However, the dissection of the relative contributions of pre- and postsynaptic components to chronic pain in the brain is difficult. Particularly, it is unclear if changes in presynaptic glutamate release related to cAMP pathway may be sufficient to cause behavioral nociceptive responses. In order to address this question, we took advantage of transgenic mice heterologously expressing an Aplysia octopamine receptor (Ap oa1) (Isiegas et al., 2008). This G protein coupled receptor selectively activates the cAMP pathway after binding of its natural ligand, octopamine (Chang et al., 2000), in the forebrain. Using whole cell recording of pyramidal neurons in the ACC, we found that activation of Ap oa1 by octopamine enhanced glutamatergic synaptic transmission (127.5±6.8% of control, n=11, P<0.01, paired t-test). The facilitatory effects was mediated activation of Ap oa1 at presynaptic site, as octopamine increased the frequency of miniature excitatory postsynaptic currents (from 3.9±0.9 Hz to 5.6±1.1Hz, n=8, P<0.01, paired t-test) and decreased paired pulse facilitation (1.48±0.09 to 1.28±0.06, n=14, P<0.05, paired t-test). Bilateral microinjection of octopamine into the ACC significantly facilitated behavioral responses to inflammatory pain (the formalin test, F(1,286) = 5.46 , P<0.037, two-way ANOVA) but not acute pain. The present study provides the first evidence linking enhanced presynaptic glutamate release in the ACC to behavioral sensitization caused by peripheral inflammation.