Central synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), is thought to be a cellular basis for multiple brain functions, such as learning and memory, drug addition, and persistent pain [1–3]. Both enhancement of presynaptic glutamate release and increased postsynaptic glutamate receptor-mediated responses have been reported to contribute to LTP of excitatory synapses and plasticity-related behavioral consequences. For example, conditional fear memory is reported to trigger LTP in lateral amygdala , where both recruitment of AMPA receptor and enhanced glutamate release are involved [5, 6]. In ventral tegmental area – nucleus accumbens pathway, drug of abuse induced postsynaptic and/or presynaptic plasticities [7, 8]. Similarly, in the anterior cingulate cortex (ACC), a brain area related to persistent pain, peripheral inflammation caused functional alterations in postsynaptic NMDA receptors and presynaptic glutamate release [9, 10]. However, the dissection of the relative contributions of pre- and postsynaptic components to these plasticity-related brain functions is difficult. Although presynaptic enhancement of glutamate release is associated with these plastic changes in brain function, there is no study available to directly address the physiological or pathological significance of presynaptic plasticity.
Among many possible candidate molecules, cyclic AMP (cAMP) is a key second messenger for synaptic plasticity and different forms of memory across different species, from invertebrates to vertebrates, including Aplysia, Drosophila, mice and rats [11–13]. Presynaptically, cAMP and cAMP-dependent protein kinase A (PKA) could target to presynaptic ion channels, such as potassium channels and the hyperpolarization-activated cation channel, or to presynaptic exocytosis machinery [14–16]. Postsynaptically, cAMP-PKA pathway is involved in AMPA receptor trafficking and activation of gene transcription that required for the late-phase of LTP [1, 17, 18]. Behaviorally, the role of cAMP in learning and memory also has been well documented. Genetic mutants lacking adenylyl cyclases (ACs), PKA, or cAMP response element binding protein (CREB) exhibit memory defects [11, 19–21].
It has been proposed that chronic pain and long-term memory share some common synaptic mechanisms [22–24]. Consistent with this notion, plasticity in sensory synapses located at pain-processing brain regions was shown to contribute to chronic pain [25, 26]. For example, in the ACC, cAMP pathway was demonstrated to be critical for synaptic plasticity and behavioral sensitization to pain. We found impaired LTP in the ACC  and attenuated behavioral sensitization in various chronic pain models in mice lacking calmodulin-stimulated AC1 and AC8 [28, 29]. Moreover, both postsynaptic and presynaptic alterations in the ACC after chronic pain are shown to be mediated by cAMP pathway [9, 10, 30]. However, genetic approaches and pharmacological approaches did not address the contribution of presynaptic vs postsynaptic mechanisms in the cortex to behavioral persistent pain. It is unclear if changes in the ACC, or even changes in presynaptic glutamate release may be sufficient to cause behavioral nociceptive responses.
While genetic and pharmacological approaches have been useful in examining the role of the cAMP pathway in pain, a combination of these approaches provides unique chance for us to investigate synaptic mechanisms related to inflammatory pain by using transgenic mice with heterologously expressed receptors impacting the cAMP pathway. We took advantage of transgenic mice heterologously expressing an Aplysia octopamine receptor (Ap oa1) . This G protein coupled receptor selectively activates the cAMP pathway after binding of its natural ligand, octopamine , in forebrain. Our results show that activation of Ap oa1 in the ACC enhanced glutamatergic synaptic transmission by increasing presynaptic glutamate release in vitro and enhanced responses to inflammatory pain in vivo by bilateral microinjection of octopamine. The current study provides direct evidence that increased presynaptic glutamate release by cAMP pathway in the ACC is sufficient for chronic pain.