In vivo effect of tramadol on locus coeruleus neurons is mediated by α2-adrenoceptors and modulated by serotonin

Tramadol is a centrally-acting analgesic endowed with opioid, noradrenergic and serotonergic properties. Various data suggest that, in addition to its analgesic effect, tramadol may have antidepressant and anxiolytic-like effects. This study investigates, through single-unit extracellular recording techniques, the in vivo effects of tramadol on locus coeruleus (LC) neurons and its possible effects on α2-adrenoceptors, opioid receptors and the 5-HT system. Tramadol produced a dose-dependent and complete inhibition of LC activity (ED50 = 2.1 mg/kg). This inhibitory effect was prevented and reversed by the selective α2-adrenoceptor antagonist, idazoxan, but not by the opioid receptor antagonist, naloxone. The inhibition of the synthesis of 5-HT by p-chlorophenylalanine and the pre-administration of the 5-HT1A receptor agonist, 8-OH-DPAT at 40 μg/kg, caused a significant potentiation of the tramadol effect decreasing the ED50 by 53% and 67% respectively. Lower doses of 8-OH-DPAT, of 1 and 4 μg/kg, did not significantly modify the tramadol effect. In summary, the results indicate that tramadol elicits an inhibitory effect on LC neurons in vivo through α2-adrenoceptors. Moreover, this effect is modulated by the 5-HT system and particularly by 5-HT1A receptors.