The Effect of Orexin‐2 and Endocannabinoid‐1 Antagonists on Neuronal Activity of Hippocampal CA1 Pyramidal Neurons in Response to Tramadol in Rats

Background: CA1, as a major structure involved in learning and memory, has been shown to be affected by tramadol addiction. Both orexin and endocannabinoid receptors express in CA1 and play an important role in drug dependency. The aim of this study was to evaluate the modulatory effects of orexin‐2 (OX2R) and endocannabinoid‐1 (CB1R) receptors on neuronal activity in CA1, in response to tramadol in rats. Materials and Methods: Male Wistar rats were divided into 8 groups (n = 6–7); saline‐dimethyl sulfoxide (DMSO), tramadol‐DMSO, saline‐TCS‐OX2‐29, saline‐AM251, tramadol‐TCS‐OX2‐29, tramadol‐AM251, saline‐TCS‐OX2‐29‐AM251, tramadol‐TCS‐OX2‐29‐AM251. Tramadol was injected intraperitoneally, and then, AM251 (1 nmol/0.3 μL), CB1R antagonist and TCS‐OX2‐29 (1 nmol/0.3 μL), OX2R antagonist, were microinjected individually or concurrently into the CA1. Using in vivo extracellular single‐unit recording, the firing of CA1 pyramidal neurons was investigated. Results: Tramadol decreased neuronal activity in CA1 (P < 0.01) but increased it after micro‐injection of DMSO. TCS‐OX2‐29 increased neuronal activity in saline group (P < 0.05) but decreased it in tramadol group. AM251 had no effect on saline group but decreased neuronal activity in tramadol group (P < 0.05). Concurrent micro‐injection of TCS‐OX2‐29 and AM251 had no effect on saline group but decreased neuronal activity in tramadol group (P < 0.05). Conclusions: Our findings suggest that neural activity in CA1 is rapidly affected by acute use of tramadol, and some of these effects may be induced through the endocannabinoid and orexin systems. Thus, the function of endocannabinoid and orexin systems in CA1 may play a role in tramadol addiction.