Galanin Acts at GalR1 Receptors in Spinal Antinociception: Synergy with Morphine and AP-5

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Abstract
The neuropeptide galanin (Gal) and its receptors (GalR1, GalR2, and GalR3) are expressed in spinal cord. We have characterized the pharmacology of the antinociceptive effects of intrathecally (i.t.) administered galanin and its analogs in the formalin test in rats, using an automated flinch detection system. Intrathecal injection of rat galanin (Gal1–29) or human galanin (Gal1–30) produced a dose-dependent inhibition of formalin-evoked flinching in phase 2, but not in phase 1. Relative potency of galanin homologs is Gal1–29 ≥ Gal1–30 > galanin-like peptide1–24 ≥ Gal2–11 = Gal 3–29 (an inactive analog). Galanin1–29 and Gal1–30 are both high-affinity agonists to GalR1/R2, whereas Gal2–11 is a GalR2 receptor agonist. Our data suggest that i.t. galanin-produced antinociception is mediated by activation of GalR1 receptors. When comparing antinociceptive effects of i.t. Gal1–29 to morphine and to 2-amino-5-phosphonopentanoic acid (AP-5, an N-methyl-d-aspartate antagonist), Gal1–29 is of intermediate potency between these two analgesic agents based on the ED50 values. An isobolographic analysis showed synergy between Gal1–29 and morphine and between Gal1–29 and AP-5 on the second phase. Fixed ratio dose combinations of morphine and Gal1–29, or AP-5 and Gal1–29 produced significantly greater antinociception than predicted from simple additivity. In summary, the present findings reveal that 1) spinal galanin produces a reliable inhibition of formalin-induced facilitated nociceptive processing, an effect possibly mediated by GalR1 receptors; and 2) galanin potentiates i.t. morphine and AP-5-induced antinociception.