Chronic inflammatory pain decreases the glutamate vesicles in presynaptic terminals of the nucleus accumbens.

Abstract

Reward system has been proved to be important to nociceptive behavior, and the nucleus accumbens (NAc) is a key node in reward circuitry. It has been further revealed that dopamine system modulates the NAc to influence the pain sensation, whereas the role of glutamatergic projection in the NAc in the modulation of chronic pain is still elusive. In this study, we used a complete Freund’s adjuvant-induced chronic inflammatory pain model to explore the changes of the glutamatergic terminals in the NAc, and we found that following the chronic inflammation, the protein level of vesicular glutamate transporter1 (VGLUT1) was significantly decreased in the NAc. Immunofluorescence staining further showed a reduced expression of VGLUT1-positive terminals in the dopamine receptor 2 (D2R) spiny projection neurons of NAc after chronic inflammatory pain. Furthermore, using a whole-cell recording in double transgenic mice, in which dopamine receptor 1- and D2R-expressing neurons can be visualized, we found that the frequency of spontaneous excitatory postsynaptic currents was significantly decreased and paired-pulse ratio of evoked excitatory postsynaptic currents was increased in D2R neurons, but not in dopamine receptor 1 neurons in NAc of complete Freund’s adjuvant group. Moreover, the abnormal expression of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex contributed to the reduced formation of glutamate vesicles. Hence, our results demonstrated that decreased glutamate release in the indirect pathway of the NAc may be a critical mechanism for chronic pain and provided a novel evidence for the presynaptic mechanisms in chronic pain regulation.