Type 2 dopamine receptors of the ventral tegmental area modulated the evoked anxiolytic effects of lateral hypothalamus in chronic pain in rat

Introduction: Chronic pain is associated with the anxiety, mediated in part by dopaminergic circuits. The ventral tegmental area (VTA) is critical area in the mesocorticolimbic dopamine system and regulate emotional and motivational behaviors. Important input to the VTA is from lateral hypothalamus (LH). However, the role of D2-like dopamine receptors of VTA in modulating of LH-anxiolytic effects during chronic pain remains unclear.
Methods: Adult male rats were unilaterally implanted with two guide cannulae in the VTA and LH. Chronic constriction injury (CCI) was used to induce neuropathic pain. Animals divided into six groups as following: control, sham, CCI, CCI+Citicoline (cholinergic precursor for LH activation), CCI+ Sulpiride (D2-like receptor antagonist), and CCI+ citicoline+ Sulpiride groups. Animals received D2-like dopamine receptor antagonists (Sulpiride, 1 µg/1µl/rat) into the VTA before intra-LH injection of Citicoline (1 µg/1µl/rat) for 7 days after CCI induction. Anxiety-like behavior was assessed using the elevated plus maze (EPM) on days 1, 3, and 7 post-CCI.
Results: The CCI surgery significantly induced anxiety-like behaviors in all experimental days (p=0.001). We observed that intra-LH injection of citicoline significantly improved anxiety-like behaviors (p=0.001). It means activation of LH via citicoline has anxiolytic effects. Intra-VTA injection of sulpiride cannot significantly change anxiety. Additionally, intra-VTA administration of sulpiride after intra-LH injection of citicoline significantly reversed the anxiolytic effects of citicoline (p=0.001).
Conclusion: The present study support the hypothesis that targeting D2-like receptor signaling in the VTA, may represent a promising strategy to alleviate anxiety related to the neuropathic pain.