Attenuation of acute and chronic effects of morphine by the imidazoline receptor ligand 2-(2-benzofuranyl)-2-imidazoline in rat locus coeruleus neurons

摘要

class="enumerated" style="list-style-type:decimal">The aim of this study was to determine if 2-(2-benzofuranyl)-2-imidazoline (2-BFI) interacts with the opioid system in the rat locus coeruleus, using single-unit extracellular recordings.In morphine-dependent rats, acute administration of the selective imidazoline receptor ligands 2-BFI (10 and 40 mg kg⁻¹, i.p. and 100 μg, i.c.v.) or valldemossine (10 mg kg⁻¹, i.p.) did not modify the naloxone-induced hyperactivity of locus coeruleus neurons compared with that observed in the morphine-dependent control group.After chronic administration of 2-BFI (10 mg kg⁻¹, i.p., three times daily, for 5 days) and morphine, naloxone-induced hyperactivity and tolerance to morphine were attenuated. This effect was not observed when a lower dose of 2-BFI (1 mg kg⁻¹, i.p.) or valldemossine (10 mg kg⁻¹, i.p.) were used.Acute administration of 2-BFI (10 and 40 mg kg⁻¹, i.p. and 100 μg, i.c.v.) but not valldemossine (40 mg kg⁻¹, i.p.) diminished the potency of morphine to inhibit locus coeruleus neuron activity in vivo (ED50 values increased by 2.3, 2.9; and 3.1 fold respectively). Similarly, the potency of Met⁵-enkephalin to inhibit locus coeruleus neurons was decreased when 2-BFI (100 μM) was applied to rat brain slices (EC50 increased by 5.6; P<0.05).The present data demonstrate that there is an interaction between 2-BFI and the opioid system in the locus coeruleus. This interaction leads to an attenuation of both the hyperactivity of locus coeruleus neurons during opiate withdrawal and the development of tolerance to morphine when 2-BFI is chronically administered. These results suggest that imidazoline drugs may prove to be useful agents for the management of opioid dependence and tolerance.