Cannabidiol in a preclinical model of neuropathic pain: an assessment of sensory, emotional and inflammatory aspects related to the modulation of pain sensitivity

Author(s)

Gleice Kelli Ribeiro da Silva Cardoso

• 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: 2022-08-05

Examining board members

Christie Ramos Andrade Leite Panissi; Norberto Cysne Coimbra; Joice Maria da Cunha; Lucas Albrechet de Souza

• Advisor: Christie Ramos Andrade Leite Panissi

Abstract

In the general population, chronic pain is 6% to 8% and affects the patient\'s quality of life. Cannabidiol (CBD) is considered a promising strategy for treating neuropathic pain. Our objective was to evaluate the systemic treatment with CBD (3 days) in rats submitted to sciatic nerve constriction (CCI), in nociceptive tests - von Frey, acetone and hot plate - (NT), open field test (OFT), the test of rotarod, and conditioned place preference (CPP), and the possible modulation of the effect of CBD on the expression of CB1 and TRPV1 receptors, in addition to the protein FosB, NeuN, inflammatory markers IBA-1 and GFAP and the interleukins IL-1&beta;, IL-6 and IL-10. 140 Wistar rats (220 g) were used, CEUA-USP: 208.1.103.58.5. The animals were submitted to two different protocols: Protocol I: the baseline of the NT was performed followed by a surgical procedure (CCI or SHAM) on day zero, the development of neuropathy was followed for three weeks (i-von Frey, ii-hot plate and iii - acetone). The TCA tests were performed on the 23rd day and the final NT test on the 24th day with 1 hour of treatment, followed by the perfusion procedure. And immunofluorescence was performed for CB1 and TRPV1 receptors in the regions of the anterior cingulate cortex (ACC), insular cortex (AIC), basolateral amygdala complex (BLA), and dorsal (HD) and ventral (HV) hippocampus. Protocol II: NT baseline and rotarod training were performed, followed by the surgical procedure on day zero, and neuropathy development was followed for three weeks by NT (i-von Frey, ii-hot plate, and iiiacetone ). The rotarod test was performed on the 18th day after the injury, and then the CPP baseline was conducted. Lidocaine (i.m. injured paw) was used as a positive and matched control in the context of longer permanence at baseline, and CBD (i.p.) was used in the context less preferred by the animal at baseline. The OFT test was performed on the 23rd day after 4 hours of treatment. On the 25th day (24 hours after the last conditioning), the rats were exposed to the CPP test without application of the drug for the test. And immunofluorescence was performed for NeuN, IBA-1, and GFAP in the ACC, BLA, and HD regions. In addition, immunohistochemistry was performed to label the expression of the FosB protein, the ACC, BLA, and HD regions. The two-way ANOVA test was used, followed by the Tukey test, P < 0.05. The results of Protocol I: Treatment with CBD for three days at different doses (0.3, 3, 10, and 30 mg/kg ip.) showed an antiallodynic effect in CCI rats in the three NT tests, as well as an anxiolytic effect in the TCA. In addition, CBD potentiated the increase in the expression of CB1 receptors in regions of the corticolimbic circuit, and the CCI surgery promoted an increase in TRPV1 receptors in the animals, and the treatment with CBD potentiated this increase in receptors. In protocol II: The results showed that the treatment with CBD promoted reversal of PCC in CCI animals and the anxiolytic effect on OFT. Furthermore, there was an increase in the expression of IBA-1, GFAP, and FosB+ in CCI animals. In contrast, NeuN expression was reduced in these animals. Treatment with CBD 3 mg/kg was able to normalize these results compared to control animals. We can conclude that treatment with CBD 3 mg/kg increased the expression of CB1 and TRPV1 receptors and increased IBA-1 and GFAP expression in the regions studied, demonstrating that the effects of CBD are linked to inflammatory markers and the participation of TRPV1 in the modulation of the effects of CBD on chronic pain. In addition, CBD treatment reversed the chronic labeling of neuronal activation and increased NeuN expression in regions where CCI surgery reduced neuronal density. Finally, we observed that CBD modulates pain aversion and induces anxiolytic-like effects in animals, promising results when we remember the relationship between chronic pain and comorbidities. These results observed in this study may explain the effects of CBD modulation in the areas of emotional modulation and perception of chronic pain. (AU)

• FAPESP's process: 18/06877-5 - Systemic treatment with canabidiol in a neuropathic pain model: evaluation of the sensorial-discriminative and emotional-motivacional components pain sensitivity
• Grantee: Gleice Kelli Ribeiro da Silva Cardoso
• Support Opportunities: Scholarships in Brazil - Doctorate