Systemic treatment with cannabidiol in high- and low-freezing Carioca rats in the chronic pain model: evaluation of pain, anxiety and BDNF expression in brain areas

Author(s)

Carolina Macêdo de Souza

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (PCARP/BC)
• Defense date: 2023-10-02

Examining board members

Christie Ramos Andrade Leite Panissi; Norberto Cysne Coimbra; Vitor de Castro Gomes; Daniela Baptista de Souza

• Advisor: Christie Ramos Andrade Leite Panissi; Jesus Landeira Fernandez

Abstract

Epidemiological studies have shown that generalized anxiety disorder (GAD) and chronic pain are highly prevalent and debilitating diseases. Concomitant to these studies, patients with GAD are highly susceptible to chronic pain. In this scenario, the incidence of studies on the neurobiological mechanisms responsible for this relationship between pain and anxiety is increasing. Despite being independent systems, there is overlap in the neural substrates corresponding to anxiety and pain, including: the hippocampus, the amygdala, and the anterior cingulate cortex (ACC). Furthermore, studies suggest that significant neuroplasticity action occurs in this interaction. However, the neurobiological mechanisms responsible for this action are not yet well known. A valid way to study these mechanisms is through the use of animal models, through preclinical research. To investigate neuroplasticity processes in nociceptive modulation, the cannabinoid system acts by modulating sensory-discriminative and affective-motivational aspects of pain and also anxiety. Therefore, this study will aim to evaluate possible interactions of chronic neuropathic pain in an animal model of contextual fear anxiety (GAD model), rats from the Carioca high and low freezing strains. As well as, analyze the effects of chronic systemic treatment with cannabidiol (CBD) in this experimental comorbidity protocol. To this end, two protocols were carried out, the first of which had the main objective of evaluating chronic pain in these animals in its multiple aspects, as well as the effect of treatment with cannabidiol. While the second was to evaluate the level of anxiety in this animal model. In both cases, the rats were evaluated for sensory-discriminative aspects (von Frey test, acetone and hot plate) before injury due to chronic constriction of the sciatic nerve (CCI) or not (SHAM) and on days 13 and 23 after surgery. Chronic treatment with CBD (5 mg/kg daily) was used for ten days, starting on the 14th postoperative day. The open field test on day 22 also assessed locomotion and anxiety-like behavior. In the first, the escape/avoidance paradigm test (PEAP) was performed on the 24th day. And in protocol 2, the animals were contextual fear conditioned (CMC) before CCI, and after chronic treatment with CBD evaluated in the fear conditioned retest (RMC). In the first study, CBD treatment had an antiallodynic effect on mechanical and thermal threshold in all strains; however, these effects were smaller in the CHF and CLF lines. Considering the emotional evaluation, we observed an anxiolytic effect in CTL+CCI and CHF+CCI after CBD treatment and increased mobility in CLF+SHAM rats. Thus, in the second study, treatment with CBD, it was observed that, in addition to the results seen previously, when in this protocol with CMC, the CHF lineage showed less recovery of the antiallodynic effect of CBD when compared to the other lines in nociceptive tests. Furthermore, in RMC the anxiolytic effect of CBD was observed in all strains and in all experimental groups, with the exception of the CHF+CCI group. In the biochemical analysis, when evaluating the expression of brain neurotrophic factor (BDNF), in protocol 1 we observed that CLF and CHF rats with CCI treated with CBD showed an increase in the level of BDNF in the dorsal hippocampus (HD) and treatment with CBD reversed this condition. The same occurred in CTL when in the ventral hippocampus (HV) and in CHF in the anterior cingulate cortex (ACC). CBD treatment reversed differences in basal lineage levels, as seen in the amygdala (AMG). While in protocol 2, we observed a condition of reduced BDNF levels in lineages with extreme anxiety in the HD structure, the same does not occur in CTL. Furthermore, CTL+CCI rats treated with CBD showed a reduction in BDNF expression, and CHF+SHAM rats treated with CBD showed an increase in BDNF levels. No differences were observed in the structure of the HV. These results suggest that the anti-allodynic and emotional mechanical effects of CBD may depend on the level of anxiety, as well as its levels of BDNF in the structures analyzed. (AU)

• FAPESP's process: 19/22120-4 - Systemic treatment with cannabidiol in rats of high and low freezing carioca lines in the chronic pain model: evaluation of pain sensitivity, affective component of pain, anxiety and its expression of BDNF
• Grantee: Carolina Macêdo de Souza
• Support Opportunities: Scholarships in Brazil - Doctorate