Persistent pain alters AMPA receptor subunit levels in the nucleus accumbens

Abstract

BackgroundA variety of pain conditions have been found to be associated with depressed mood in clinical studies. Depression-like behaviors have also been described in animal models of persistent or chronic pain. In rodent chronic neuropathic pain models, elevated levels of GluA1 subunits of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the nucleus accumbens (NAc) have been found to inhibit depressive symptoms. However, the effect of reversible post-surgical pain or inflammatory pain on affective behaviors such as depression has not been well characterized in animal models. Neither is it known what time frame is required to elicit AMPA receptor subunit changes in the NAc in various pain conditions.ResultsIn this study, we compared behavioral and biochemical changes in three pain models: the paw incision (PI) model for post-incisional pain, the Complete Freund’s Adjuvant (CFA) model for persistent but reversible inflammatory pain, and the spared nerve injury (SNI) model for chronic postoperative neuropathic pain. In all three models, rats developed depressive symptoms that were concurrent with the presentation of sensory allodynia. GluA1 levels at the synapses of the NAc, however, differed in these three models. The level of GluA1 subunits of AMPA-type receptors at NAc synapses was not altered in the PI model. GluA1 levels were elevated in the CFA model after a period (7 d) of persistent pain, leading to the formation of GluA2-lacking AMPA receptors. As pain symptoms began to resolve, however, GluA1 levels returned to baseline. Meanwhile, in the SNI model, in which pain persisted beyond 14 days, GluA1 levels began to rise after pain became persistent and remained elevated. In addition, we found that blocking GluA2-lacking AMPA receptors in the NAc further decreased the depressive symptoms only in persistent pain models.ConclusionOur study shows that while both short-term and persistent pain can trigger depression-like behaviors, GluA1 upregulation in the NAc likely represents a unique adaptive response to minimize depressive symptoms in persistent pain states.

Persistent neuropathic pain increases synaptic GluA1 subunit levels in core and shell subregions of the nucleus accumbens

“…In these studies on rewards, the length of time required to increase GluA1 levels is in general compatible with the time course found in our study. Similarly, in a previous study on AMPA receptor trafficking, GluA1 upregulation at the NAc synapse is found to occur after pain has become persistent or chronic [52]. Thus, we speculate that GluA1 upregulation in the core and shell of NAc in persistent pain states may represent a form of homeostatic plasticity in the reward system.…”

“…A previous study has shown that increases in GluA1 levels at the NAc synapse do not manifest until at least 7 days after SNI, suggesting that persistent pain, rather than acute nerve injury, triggers the synaptic targeting of GluA1 subunits [52]. More importantly, increased GluA1 delivery to the NAc synapse has also been demonstrated in a persistent inflammatory pain model that does not involve nerve injuries [52]. Thus, we believe that chronic pain, rather than nerve injury, causes the GluA1 increases observed in the current study.…”

“…On the other hand, GluA2-lacking AMPA receptors, predominantly formed by GluA1 homomers, conduct Ca 2+ and are also known as Ca 2+ -permeable AMPA receptors (CPARs) [16, 35]. Chronic pain has been shown to selectively increase GluA1 subunit levels at the synapse in the NAc, likely through increased trafficking, and this selective increase in GluA1 subunits leads to the formation of CPARs [24, 51]. CPARs, in turn, can regulate the affective symptoms of chronic pain [24].…”

AMPAkines Target the Nucleus Accumbens to Relieve Postoperative Pain

“…1A). 35,39 This sensory hypersensitivity lasted up to 4 days after incision, and it resolved by the 7 th day post-incision 18,39 (Fig. 1A).…”

“…18,35,39 Briefly, rats were anaesthetized with Isoflurane anesthesia (1.5 to 2%), and the plantar surface of the right hind paw was sterilized and prepared. A 1.5 cm longitudinal incision was made with a number 10 scalpel, through skin and fascia of the right plantar aspect of the paw.…”