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 (Gal_1–29) or human galanin (Gal_1–30) produced a dose-dependent inhibition of formalin-evoked flinching in phase 2, but not in phase 1. Relative potency of galanin homologs is Gal_1–29 ≥ Gal_1–30 > galanin-like peptide_1–24 ≥ Gal_2–11 = Gal _3–29 (an inactive analog). Galanin_1–29 and Gal_1–30 are both high-affinity agonists to GalR1/R2, whereas Gal_2–11 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. Gal_1–29 to morphine and to 2-amino-5-phosphonopentanoic acid (AP-5, an N-methyl-d-aspartate antagonist), Gal_1–29 is of intermediate potency between these two analgesic agents based on the ED₅₀ values. An isobolographic analysis showed synergy between Gal_1–29 and morphine and between Gal_1–29 and AP-5 on the second phase. Fixed ratio dose combinations of morphine and Gal_1–29, or AP-5 and Gal_1–29 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.