NEW HIGH-AFFINITY PEPTIDE ANTAGONISTS TO THE SPINAL GALANIN RECEPTOR

1 The role of endogenous galanin in somatosensory processing has been studied with galanin receptor antagonists. The new galanin receptor li gands C7, M32, M38 and M40 bind with high affinity (K-d in nanomolar r ange) to spinal cord galanin receptors and possess oxidative stability as compared to earlier generations of peptide ligands. These peptides have been examined in the spinal flexor reflex model where exogenous galanin exhibited biphasic excitatory and inhibitory effects. 2 Intrat hecal administration of C7 [galanin(1-13)-spantide] and M32 [galanin ( 1-13)-neuropeptide Y(25-36) amide] blocked facilitation of the nocicep tive flexor reflex induced by 30 pmol intrathecal galanin in decerebra te, spinalized rats in a dose-dependent manner, thus behaving as antag onists of the galanin receptor. In contrast, M38 [galanin(1-13)-(Ala-L eu)(3)-Ala amide] and M40 [galanin(1-13)-Pro-Pro-(Ala-Leu)(2)Ala amide ], exhibited only weak antagonism at high doses in this model. Moreove r, lower doses of M40 potentiated galanin-induced reflex facilitation. C7 was neurotoxic at high doses in the rat spinal cord.3 M32 and C7 w ere potent antagonists of galanin receptors in rat spinal cord, in cor relation with their in vitro binding characteristics. In contrast, M38 and M40, despite their high in vitro affinity, exhibited only very we ak antagonism. Moreover, M40 may also behave as a partial agonist. 4 P revious studies have shown that the galanin receptor may be heterogene ous. The discrepancy between in vitro binding and in vivo antagonistic potency of M38 and M40 may also suggest the presence of different gal anin receptor subtypes within the rat spinal cord. However, other expl anations for the discrepancy, such as differences in metabolic stabili ty, diffusion rates and penetration to the site of action are also pos sible.