Effects of selective orexin receptor‐2 and cannabinoid receptor‐1 antagonists on the response of medial prefrontal cortex neurons to tramadol

Abstract

Tramadol is widely used to control pain in various diseases, but the relevant mechanisms are less known despite the severe risks of abuse. The medial prefrontal cortex (mPFC) is one of the critical centers of the reward system. Studies have shown that orexins and endocannabinoids are likely to play an important role in addiction.In this study, the effect of orexin receptor-2 (OX2R) and endocannabinoid receptor-1 (CB1R) blockade on the neuronal activity of mPFC was investigated in response to tramadol in male rats. Tramadol was injected intraperitoneally, and its effects on the firing of mPFC pyramidal neurons were investigated using in vivo extracellular single-unit recording. Tramadol affected the pyramidal neuronal activity of the mPFC. AM251 (18 nmol/4 μl), as a selective CB1R antagonist, and TCS-OX2-29 (50 nmol/4 μl), as a selective OX2R antagonist, individually or simultaneously were microinjected into the lateral ventricle of the brain (intracerebroventricular, ICV). The results showed that the ratio of neurons with the excitatory/inhibitory or no responses was significantly changed by tramadol (p < .05). These changes were prevented by blockade of CB1Rs alone or blockade of OX2Rs and CB1Rs simultaneously (p < .05). However, blockade of these receptors in the vehicle group had no significant effect on neuronal activity.The findings of this study indicate the potential role of orexin and endocannabinoid systems in mediating the effects of tramadol in mPFC and the possible interaction between the two systems via OX2 and CB1 receptors. However, further studies are needed to identify these effects by examining intracellular signaling.

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

“…Nevertheless, novel pharmacological studies have exemplified the ways in which the two systems can interface in vivo: i) administration of the CB1‐R antagonist AM251 alters orexin‐A induced food intake; 203 ii) OX1‐R is involved in the rewarding effects of CB1‐R, and OX1‐R antagonists block self‐administration of synthetic cannabinoids (i.e., WIN55,212‐2 ); 204 and iii) OX2‐R modulate CB1‐R‐mediated antinociception and anxiolytic‐like effects of tetrahydrocannabinol 26,205 . The role of CB1‐R/OX2‐R pharmacology in analgesia was also assessed in presence of the MOR agonist tramadol , demonstrating that the blockage of neural activity changes by simultaneous administrations of CB1‐R/OX2‐R antagonists ( AM251 and TCS‐OX2‐29 , respectively) 206 …”

“…26,205 The role of CB1-R/OX2-R pharmacology in analgesia was also assessed in presence of the MOR agonist tramadol, demonstrating that the blockage of neural activity changes by simultaneous administrations of CB1-R/OX2-R antagonists (AM251 and TCS-OX2-29, respectively). 206 Consequently, these studies have garnered further interest in designing and developing bivalent ligands for the OX-R/CB-R heteromers and small molecules with dual-target functional profiles (mixed combinations of agonismantagonism) to elucidate the therapeutic potential of simultaneously targeting the orexinergic and cannabinoid systems. More recently, in 2021, OX1-R was identified as a target for cannabidiol (CBD), a major component of cannabis sativa for which beneficial therapeutic profiles have been postulated without a clear identification of molecular targets/mechanisms.…”