Effects Of Musical Environment On Anxiety Disorder Associated With Neuropathic Pain

Patients with chronic pain not only suffer intolerable ongoing pain but also undergo accompanying cognitive impairment and emotional disorders.Music has been used as an adjuvant therapy to relieve pain and anxiety with variable effectiveness in clinic.However,little is known about the underlying mechanisms.Prefrontal cortex is reported to be a critical area in the processing of both chronic pain and emotional stimulus.But its role in chronic pain induced anxiety is unclear.In the present study,we investigated the effects of musical environment on anxiety-like behaviors in a rat model of neuropathic pain with spared nerve injury?SNI?.The rats showed apparent anxiety-like behaviors in both elevated-plus maze test and open field test at the 8^th week after SNI surgery.Thus,in the elevated-plus maze test,the percentage of entering open arms significantly?p<0.001?decreased in SNI rats,so did the time spent in open arms.The number of entries to central area decreased to 45%?±5%,n=15?of sham control?n=13?in the open field test,while overall motor activity?i.e.,total distance?was unaffected.The anxiety-like behaviors were not observed with the SNI rats that received 6 weeks of classical music exposure?Mozart Sonata K.448 and Beethoven's fur Elise,65dB,12h/day,dark cycle?.The performance of the music group in both open field test and elevated-plus maze test showed no significant difference from the sham control group,indicating that the music effectively prevented or reversed anxiety induced by chronic pain condition.No effect was observed with white noise.Meanwhile,we also found that this anxiolytic effect of music lasted for one week after the cessation of music treatment.2 weeks of music exposure showed the same anti-anxiety effect.To explore the underlying mechanisms,Western blot analysis was performed to examine the changes of serotonin transporter?SERT?in brain areas associated with anxiety disorder.We found that there was a significant increase in the expression of SERT in the prefrontal cortex in SNI rats.However,the SNI rats treated with music did not show such an increase in the SERT expression,suggesting that music effectively suppressed chronic pain-induced increase in SERT expression in prefrontal cortex.The anxiety-like behaviors of SNI rats were effectively reversed by sub chronic?15 days?treatment with citalopram?10mg/kg,i.p.?,an selective SERT inhibitor,which proved the critical role of SERT in the modulation of anxiety associated with neuropathic pain.Recording of local field potentials showed that SNI rats had enhanced increase of?power in medial prefrontal cortex in anxiety tests,as well as the phase coherence between medial prefrontal cortex and ventral hippocampus.SNI rats treated with music did not show such enhancements,suggesting music effectively suppressed the abnormal activity of?oscillation in the medial prefrontal cortex and ventral hippocampus in neuropathic rats.The results indicated that music exerts its anxiolytic effect by suppressing incresed SERT expression in prefrontal cortex and enhanced?oscillation in meidal prefrontal cortex and ventral hippocampus induced by neuropathic pain.In summary,our study demonstrated the effectiveness of musical environment in alleviating the anxiety-like behaviors in an animal model of neuropathic pain.Prefrontal cortex may play an important role in the anxiolytic effect of the music.Our data provide important information for understanding the central mechanisms of music-based therapeutic intervention for anxiety disorders in patients with chronic pain.