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.

Pain has been found to promote reward‐seeking behaviors, which might be a consequence of modulated brain activities in the reward neural circuitry in a painful state. The present study investigated how pain affected reward processing and reward‐related neural activities using fMRI technique. A total of 50 healthy participants were recruited and used for data analyses, with half being treated with topical capsaicin cream and the other half with hand cream (treatment: pain or control). The participants were asked to perform a card‐guessing game when their brain activities responding to feedbacks (outcome: win or loss) were recorded. Behavioral results showed that participants in pain group overestimated their correct choices in the card‐guess game. Whole‐brain fMRI analysis revealed that the main effect of outcome (win vs. loss) activated a typical network of the reward neural circuitry, including the medial prefrontal cortex (mPFC) and the bilateral nucleus accumbens (NAcc). Importantly, the region of interest analysis revealed a significant interaction of treatment and outcome in the mPFC, with increased mPFC neural activity responding to win outcome in pain condition. Moreover, the functional connectivity between the mPFC and the NAcc was decreased in pain condition. We conclude that the pain‐induced modulation of the mPFC activity could result in alterations of both the emotional response to and the cognitive evaluation of reward.

Neurons in frontal and parietal cortex encode task variables during decision-making, but causal manipulations of the two regions produce strikingly different results. For example, silencing the posterior parietal cortex (PPC) in rats and monkeys produces minimal effects in perceptual decisions requiring integration of sensory evidence, but silencing frontal cortex profoundly impairs the same decisions. Here, we tested, for the first time, the causal roles of the rat frontal orienting field (FOF) and PPC in economic choice under risk. On each trial, rats chose between a lottery and a small but guaranteed surebet. The magnitude of the lottery was independently varied across trials and was indicated to the rat by the pitch of an auditory cue. As in perceptual decisions, both unilateral and bilateral PPC muscimol inactivations produced minimal effects. FOF inactivations produced substantial changes in behavior even though our task had no working memory component. We quantified control and bilateral inactivation behavior with a multi-agent model consisting of a mixture of a ‘rational’ utility-maximizing agent (U = Vρ) with two ‘habitual’ agents that either choose surebet or lottery. Silencing PPC produced no significant shifts in any parameters relative to controls. Effects of FOF silencing were best explained by a decrease in ρ, the exponent of the utility function. This effect was parsimoniously explained by a dynamical model where the FOF is part of network that performs sensory-to-value transformations.