Neuroanatomical characterization of imidazoline I-2 receptor agonist-induced antinociception

Chronic pain is a significant public health problem with a lack of safe and effective analgesics. The imidazoline I-2 receptor (I2R) is a promising analgesic target, but the neuroanatomical structures involved in mediating I2R-associated behaviors are unknown. I(2)Rs 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.