Effect of chronic treatment with fluoxetine or cannabidiol on the comorbidity between neuropathic pain and depression in rats: investigation of cannabidiol psychopharmacological mechanisms

Abstract

HYPOTHESIS: Neuropathic pain is one of the major health problems that can affect more than 20% of adults. Chronic pain is the primary cause of withdrawal from work, thus generating a huge burden on public health. In this way, it becomes a standard and also challenging condition, regarding the origin and treatment of chronic pain and neurological comorbidities triggered by this pathology. Also, studies are needed to address the pathophysiological and psychopharmacological basis of comorbidity between chronic pain and depression, to better understand and treat this comorbidity. Cannabidiol (CBD) is currently being investigated to evaluate its effects in the treatment of various neurological disorders such as epilepsy, Parkinson's disease and schizophrenia. Animal models also point to the effectiveness of CBD in attenuating anxiety and panic-related behaviours. Thus, we will evaluate the effect of CBD and compare it with a standard antidepressant, fluoxetine, in animal models related to depression and neuropathic pain. INVESTIGATION 1: The effect of intraperitoneal chronic treatment of 10% DMSO or CBD at doses of 10, 30 or 60 mg/kg in animals with chronic constriction induced neuropathic pain (CCI) of the sciatic nerve will be studied. Neuropathic animals will be evaluated in the forced swimming test and the sucrose preference test (1%), both related to depression. Immediately afterwards, mechanical allodynia and cold hypersensitivity will be studied by the von Frey test and acetone test, respectively. They will be checked 21 days after the CCI or Sham procedure ("false operated"). Chronic treatment (21 days) with CBD will be initiated on the same day of the CCI or sham or 21 days after the referred surgery to evaluate the influence of these treatments on the genesis and maintenance/aggravation of this comorbidity between chronic pain and depression in an Experimental Model with rodents. INVESTIGATION 2: In order to pharmacologically validate and compare the effect of the antidepressant fluoxetine with the CBD, chronic treatment with fluoxetine at 20 mg/kg will be performed, and then we will evaluate the responses related to depression in the forced swimming test and the sucrose preference test (1%) in animals with neuropathic pain. Chronic treatment (21 days) with fluoxetine will be initiated on the same day as CCI or sham or 21 days after the surgery. INVESTIGATION 3: The next step will be to investigate the pharmacological mechanisms that may be associated with the effects of CBD on animal models related to depression (forced swimming test and sucrose preference) in animals with neuropathic pain. For this, on the day of the forced swimming test or sucrose preference, pre-treatment of the animals will be performed with WAY-100635, a 5-HT1A serotonergic receptor antagonist, to evaluate the effects of CBD in animals with Neuropathic pain and submitted to tests related to depression depend on the activation of this type of serotoninergic receptor. (AU)