Plastic change of prefrontal cortex mediates anxiety-like behaviors associated with chronic pain in neuropathic rats

Abstract

Clinical studies show that anxiety and chronic pain are concomitant. The neural basis for the comorbidity is unclear. The prefrontal cortex (PFC) has been recognized as a critical area for affective disorders and chronic pain modulation. In this study, we examined the role of the PFC in the pathogenesis of anxiety associated with chronic pain in a rat model of neuropathic pain with spare nerve injury (SNI). The SNI rats showed apparent anxiety-like behaviors in both open field (OF) test and elevated-plus maze (EPM) test eight weeks after surgery. Thus, the number of entries to the central area in the OF decreased to 45% (±5%, n = 15) of sham control (n = 17), while the overall motor activity (i.e., total distance) was unaffected. In the EPM, the percentage of entries into the open arms significantly (p < 0.001) decreased in SNI rats (SNI: 12.58 ± 2.7%, n = 15; sham: 30.75 ± 2.82%, n = 17), so did the time spent in the open arms (SNI: 4.35 ± 1.45%, n = 15; Sham: 11.65 ± 2.18%, n = 17). To explore the neural basis for the association between anxiety and chronic pain, local field potentials (LFPs) were recorded from the medial PFC (mPFC) and ventral hippocampus. In SNI rats, there were significantly greater increases in both theta-frequency power in the mPFC and theta-frequency synchronization between the mPFC and ventral hippocampus, when animals were displaying elevated anxiety-like behaviors in avoiding anxiogenic regions in EPM and OF chamber. Western blot analyses showed a significant elevation of serotonin transporter expression in the anxious SNI rats. Inhibition of serotonin transporter effectively alleviated anxiety-like behaviors following sub-chronic (15 days) treatment with systemic citalopram (10 mg/kg/day, intraperitoneally). Moreover, the anxiety-like behaviors in the SNI rats were also suppressed by direct mPFC application of serotonin. Taken together, we conclude that the plasticity of serotonin transmission in the mPFC likely contribute to the promotion of anxiety state associated with neuropathic pain.

Behavioral, Biochemical and Electrophysiological Changes in Spared Nerve Injury Model of Neuropathic Pain

“…Anxiety-like behavior following SNI has been found in both rats and mice. In rats, anxiety-like behavior has been observed in the elevated plus-maze and open field tests at different postoperative times: day 14 [40], day 21 [40,41], day 28 [34,42], days 20-40 [43] and it continues for between 8 weeks [44] and 24 weeks [38]. Interestingly, other studies have failed to observe anxiety-like behavior in the rats subjected to SNI using the same tests over a long observation period ranging from 7 to 19 weeks [27,45].…”

“…Intriguingly, Guida et al [33] observed that 30 days-SNI mice showed an overall decreased activity of mPFC pyramidal neurons with a subsequent reduced level of glutamate correlated with pain-related depression-like behavior, cognitive impairments, and obsessive-compulsive-like disorder. Sang et al [44] suggested that the mPFC endures plastic changes after SNI (15 days), as indicated by an elevation of serotonin transporter (SERT) expression, as well as, a greater enhancement of its local field potential (LFP) theta-frequency associated with anxiety-like behavior in avoiding anxiogenic environment. The anxiety-like behaviors of the SNI rats were effectively suppressed by local application of serotonin to the mPFC.…”

Chemokine Signaling in Chemotherapy-Induced Neuropathic Pain

“…Thus, decreased microglia activation reduced neuropathic pain behavior and the levels of inflammatory mediators, depending on the presence or absence of a depressive phenotype. Other studies have indicated that that anxiety and chronic pain are concomitant, but neural substrates for their comorbidity are unclear [90].…”

Lacrimal gland excision in male and female mice causes ocular pain and anxiety-like behaviors

“…Human studies have shown a positive correlation between DED severity and symptoms of anxiety 7,[60][61][62] . While there have been some reports of increased signs of anxiety in chronic pain models, other reports have not found a significant effect of pain on anxiety measures [63][64][65][66][67][68][69][70] . Using the elevated plus maze, single LGE reduced open arm time only in female mice, whereas double LGE reduced open arm time in both female and male mice.…”