Neuroanatomical characterization of imidazoline I2 receptor agonist-induced antinociception

Abstract

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 CFA- and CCI-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.

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