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Page 4 of 8 Toyoda. Neuroimmunol Neuroinflammation 2018;5:40 I http://dx.doi.org/10.20517/2347-8659.2018.48

synaptotagmin, syntaxin and synaptosome-associated protein-25 (SNAP-25) are involved in the synaptic
plasticity in the central nervous system [39-41] . Increases in synaptic vesicle proteins including synapsin,
synaptophysin and synaptotagmin contribute to the enhanced synaptic potentiation in the hippocampal
neurons [42,43] . Furthermore, in the spinal cord of chronic neuropathic pain rat models, the number of
[44]
presynaptic boutons that are synaptophysin-immunoreactive was significantly increased . In synaptosomal
fractions obtained from the medial prefrontal cortex of neuropathic pain rat models, expression levels of
presynaptic proteins (including synaptotagmin, synaptophysin, syntaxin, synaptobrevin and SNAP-25) were
[45]
significantly enhanced, compared to those obtained from sham rats . In addition, the electron microscopy
revealed that synaptic vesicles in the synaptosomes were significantly increased in the medial prefrontal
[45]
cortex of neuropathic pain rat models . These observations suggest that the enhancement of both the
number and availability of synaptic vesicles play critical roles in the enhancement of excitatory synaptic
transmission in the medial prefrontal cortex of neuropathic pain rat models.

SOS3-interacting protein 3 (SIP3), which is known as a SNAP25-interacting protein 30, was first identified
[46]
in the hair cells of guinea pig cochlea . This novel protein is composed of 266 amino acids is one of
the soluble N-ethylmaleimide-sensitive factor attachment protein receptors and plays essential roles for
[47]
regulated exocytosis of synaptic vesicles in neurotransmission . SIP30 is highly expressed in various brain
[46]
regions including the cortex . SIP30 was previously shown to be associated with the modulation of pain.
For example, the increase in the expression of SIP30 in the spinal cord of chronic constriction injury rats
[48]
was involved in the formation and maintenance of neuropathic pain . In addition, the same group revealed
that chronic constriction injury induced an increase of SIP30 in both sides of the ACC together with the
[49]
behavioral hypersensitivity . Interestingly, they showed that knockdown of SIP30 by lentiviral vector-
mediated short hairpin RNA in the ACC significantly suppressed not only the behavioral hypersensitivity
but also the glutamate release within the ACC. These results suggest that SIP30 is critical for the increased
excitatory synaptic transmission in the ACC.

Presynaptic changes in ACC synapses of animals with disease-related pain
Diabetes mellitus
Diabetes mellitus is known as one of metabolic diseases and is caused by deficiency or diminished
effectiveness of endogenous insulin. The high blood sugar levels resulting from the reduced insulin produces
several symptoms such as increased hunger, frequent urination and increased thirst. If left untreated,
[50]
diabetes mellitus causes many acute and chronic complications . Peripheral neuropathy is the most
[51]
common and debilitating complication of diabetic patients . Thus, a number of studies revealed that
diabetes-related plasticity occurs in the spinal nociceptive neurons [52-54] . In addition to the spinal cord,
diabetes mellitus causes plasticity in the supraspinal brain regions pertinent to the processing of pain
information [55,56] . In the ACC of the streptozotocin-induced diabetic rats, there was a significant reduction
[56]
in paired-pulse facilitation compared to the control mice , suggesting that an enhanced presynaptic
glutamatergic synaptic transmission occurs in the ACC neurons of the diabetic mice. Therefore, it is strongly
suggested that presynaptic changes in the ACC are critically involved in the diabetes-induced pain.

Hypothyroidism
Two thyroid hormones, triiodothyronine (T3) and thyroxine (T4), are primarily responsible for regulation
[57]
of metabolism and play essential roles in the development and activity of the central nervous system .
The thyroid status of neonates and children has a significant long-term impact on locomotor activity
[57]
and cognition . Indeed, congenital hypothyroidism, which is characterized by deficiencies in thyroid
[58]
hormone production in newborn infants, causes mental retardation in children . In addition, adult-onset
hypothyroidism which is caused by insufficiency of thyroid hormones in the adulthood decreases cognitive
[60]
[59]
functions . The interaction between pain and thyroid hormones has been progressively elucidated . In
[61]
athyreotic patients, the pain sensitivity was associated with the thyroid status . It has also been reported