Neuroanatomical characterization of imidazoline I₂ receptor agonist-induced antinociception

Chronic pain is a significant public health problem with a lack of safe and effective analgesics. The imidazoline I₂ receptor (I₂R) is a promising analgesic target, but the neuroanatomical structures involved in mediating I₂R-associated behaviors are unknown. I₂Rs are enriched in the arcuate nucleus, dorsal raphe (DR), interpeduncular nucleus, lateral mammillary body, medial habenula, nucleus accumbens (NAc) and paraventricular nucleus; thus, this study investigated the antinociceptive and hypothermic effects of microinjections of the I₂R agonist 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI). In rats, intra-DR microinjections produced antinociception in complete Freund's adjuvant- and chronic constriction injury-induced pain models. Intra-NAc microinjections produced antinociception and increased noxious stimulus-associated side time in a place escape/avoidance paradigm. Intra-NAc pretreatment with the I₂R antagonist idazoxan but not the D1 receptor antagonist SCH23390 or the D2 receptor antagonist raclopride attenuated intra-NAc 2-BFI-induced antinociception. Intra-NAc idazoxan did not attenuate systemically administered 2-BFI-induced antinociception. Microinjections into the other regions did not produce antinociception, and in none of the regions produced hypothermia. These data suggest that I₂R activation in some but not all I₂R-enriched brain regions is sufficient to produce antinociception and supports the theory that different I₂R-associated effects are mediated via distinct receptor populations, which may in turn be distributed differentially throughout the CNS.