Cannabidiol in the dorsal hippocampus attenuates emotional and cognitive impairments related to neuropathic pain: The role of prelimbic neocortex-hippocampal connections

Background and purpose: Chronic neuropathic pain (NP) is commonly associated with cognitive and emotional impairments. Cannabidiol (CBD) presents a broad spectrum of action with a potential analgesic effect. This work investigates the CBD effect on comorbidity between chronic NP, depression, and memory impairment.

Experimental approach: The connection between the neocortex and the hippocampus was investigated with biotinylated dextran amine (BDA) deposits in the prelimbic cortex (PrL). Wistar rats were submitted to chronic constriction injury (CCI) of the sciatic nerve and CA₁ treatment with CBD (15, 30, 60 nmol).

Key results: BDA-labeled perikarya and terminal buttons were found in CA₁ and dentate gyrus. CCI-induced mechanical and cold allodynia increased c-Fos protein expression in the PrL and CA₁. The number of astrocytes in PrL and CA₁ increased, and the number of neuroblasts decreased in CA₁. Animals submitted to CCI procedure showed increasing depressive-like behaviors, such as memory impairment. CBD (60 nmol) treatment decreased mechanical and cold allodynia, attenuated depressive-associated behaviors, and improved memory performance. Cobalt chloride (CoCl₂: 1 nM), WAY-100635 (0.37 nmol), and AM251 (100 nmol) intra-PrL reversed the effect of CA₁ treatment with CBD (60 nmol) on nociceptive, cognitive, and depressive behaviors.

Conclusion: CBD represents a promising therapeutic perspective in the pharmacological treatment of chronic NP and associated comorbidities such as depression and memory impairments. The CBD effects possibly recruit the CA₁-PrL pathway, inducing neuroplasticity. CBD acute treatment into the CA₁ produces functional and molecular morphological improvements.