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Page 2 of 8 Toyoda. Neuroimmunol Neuroinflammation 2018;5:40 I http://dx.doi.org/10.20517/2347-8659.2018.48

Sensory inputs from the periphery are conveyed to the dorsal root ganglion and then to the spinal dorsal
horn (SDH). The SDH neurons send ascending projection to the thalamus. Subsequently, the outputs from
the thalamus synapse on the neurons in the ACC, amygdala and other cortices including the somatosensory
and insular cortex [3,5,14,15] [Figure 1].

With regard to the synaptic mechanisms of chronic inflammatory and neuropathic pain, it has been
proposed that changes in both the presynaptic and postsynaptic function play essential roles [8,16] . To date,
a number of studies have shown that tissue injury- or nerve damage-caused central sensitization, a similar
[7,8]
phenomenon like long-term potentiation (LTP), in the ACC could contribute to the persistent pain . Since
it has generally been believed that postsynaptic mechanisms are crucial for the LTP expression, postsynaptic
changes following nerve injury in the ACC synapses have been primarily studied to understanding the
mechanisms of chronic pain. In behavioral experiments using genetic and pharmacological approaches,
inhibiting postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-
[17]
mediated synaptic plasticity is shown to be sufficient to produce analgesic effects . These data indicate that
postsynaptic LTP in the ACC is involved in chronic pain. Compared to studies focusing on postsynaptic
mechanisms, those focusing on presynaptic mechanisms which contribute to persistent pain are relatively
few. However, presynaptic changes in the ACC underlying chronic pain have been progressively elucidated
in recent years. In this review, I will discuss studies regarding the molecular mechanisms that play pivotal
roles in chronic pain and presynaptic form of long-term potentiation (pre-LTP) in the ACC. In addition, I
discuss presynaptic changes associated with disease-related pain in the ACC.

Molecular mechanisms of presynaptic changes in the ACC following nerve injuries and
inflammation
Calcium/calmodulin-stimulated adenylyl cyclase
Cyclic adenosine monophosphate (cAMP) is a nucleotide that acts as a key second messenger in a number
of physiological functions including chronic pain, learning and memory, emotional fear and drug abuse [18,19] .
The adenylyl cyclase (AC) is the important enzyme that converts ATP to cAMP. The AC family is composed
of nine membrane-bound isoforms (AC1-9) and one soluble isoform (sAC). These isoforms are differentially
[20]
distributed in the body, and each AC isoform has distinct physiological functions . Among AC1-9 and sAC,
[20]
AC1 and AC8 are the key AC isoforms that respond positively to calcium-calmodulin . AC1 is 4 to 5 times
more sensitive to an increase in calcium concentration than AC8. It has been shown that AC1 is abundantly
[21]
expressed in the mouse ACC neurons . We have previously demonstrated that deletion of AC1 and AC8
[22]
genes significantly reduced pain sensitization in mice with chronic inflammatory pain and in those
with chronic neuropathic pain [16,21] . In ACC synapses of mice with inflammatory pain, the enhancement
[22]
of presynaptic transmitter release was suppressed by inhibition of AC1 and/or AC8 . Thus, presynaptic
AC1 and/or AC8 could be the key molecules that contribute to the enhancement of both the probability of
transmitter release and the number of available vesicles in response to inflammatory pain. Subsequently,
AC1 and/or AC8 would activate protein kinase A (PKA) and then phosphorylate cAMP response element
[21]
binding protein . In addition, we have shown that AC1 plays essential roles in both the presynaptic and
[16]
postsynaptic changes in ACC synapses in the mouse spinal nerve ligation model of neuropathic pain .
An aplysia octopamine receptor (Ap oa1) is G protein-coupled and selectively activates cAMP/PKA
[23]
pathway . By using transgenic mice heterologously expressing Ap oa1, we have previously examined
whether and how cAMP in the ACC synapses is involved in the presynaptic modulation of neurotransmitter
release. We found that the activation of Ap oa1 by octopamine augmented glutamatergic synaptic
transmission in the ACC synapses . Also, behavioral responses to inflammatory pain were apparently
[24]
[24]
facilitated by bilateral microinjection of octopamine into the ACC . These findings provide the evidence
that the presynaptic modulation by cAMP contributes to chronic pain caused by peripheral inflammation.
Therefore, AC1 may be potential therapeutic targets for treatment of chronic pain. Indeed, intraperitoneal or