Involvement of cannabinoid receptors and neuroinflammation in early sepsis: Implications for posttraumatic stress disorder

Abstract

Sepsis is associated with several comorbidities in survivors, such as posttraumatic stress disorder (PTSD). This study investigated whether rats that survive sepsis develop the generalization of fear memory as a model of PTSD. Responses to interventions that target the endothelin-1 (ET-1)/cannabinoid system and glial activation in the initial stages of sepsis were evaluated. As a control, we evaluated hyperalgesia before fear conditioning. Sepsis was induced by cecal ligation and puncture (CLP) in Wistar rats. CLP-induced sepsis with one or three punctures resulted in fear generalization in the survivors 13 and 20 days after the CLP procedure, a process that was not associated with hyperalgesia. Septic animals were intracerebroventricularly treated with vehicle, the endothelin receptor A (ET_A) antagonist BQ123, the cannabinoid CB₁ and CB₂ receptor antagonists AM251 and AM630, respectively, and the glial blocker minocycline 4 h after CLP. The blockade of either CB₁ or ET_A receptors increased the survival rate, but only the former reversed fear memory generalization. The endothelinergic system blockade is important for improving survival but not for fear memory. Treatment with the CB₂ receptor antagonist or minocycline also reversed the generalization of fear memory but did not increase the survival rate that was associated with CLP. Minocycline treatment also reduced tumor necrosis factor-α levels in the hippocampus suggesting that neuroinflammation is important for the generalization of fear memory induced by CLP. The influence of CLP on the generalization of fear memory was not related to Arc protein expression, a regulator of synaptic plasticity, in the dorsal hippocampus.

Keywords: Endocannabinoids; Endothelin; Fear conditioning; Glial activation; Posttraumatic stress disorder; Sepsis.