The galanin antagonist M35 has intrinsic agonistic activity in the dorsal root ganglion

Abstract

The chimeric peptide M35 (galanin(1-3)-bradykinin(2-9)amide) is a high-affinity galanin receptor ligand which acts as a galanin receptor antagonist in many experimental models such as the flexor reflex and chronic constriction injury in rat. However, more recently there have been conflicting reports that M35 may act as a galanin receptor agonist in certain systems. Here we demonstrate that in the absence of endogenous galanin M35 has an agonistic effect, significantly enhancing neurite outgrowth from cultured adult mouse dorsal root ganglion neurons, albeit at a lower potency than galanin peptide itself. However, in the presence of galanin its agonistic activity is masked and thus it appears to act as a galanin receptor antagonist.

Subarachnoid transplantation of immortalized galanin‐overexpressing astrocytes attenuates chronic neuropathic pain

“…The exact reasons are unclear. However, in the absence of endogenous galanin in the galanin‐knockout mouse, M35 has an agonistic effect, whereas in the presence of galanin, its agonistic activity is masked and it acts as an antagonist (Mahoney et al, 2003). Therefore, as found in group 5, animals had a significant increase of galanin levels in CSF after grafted with IAST/GAL cells and displayed pronounced analgesic effects, which were partially reversed by the intrathecal injection of M35.…”

The axotomy‐induced neuropeptides galanin and pituitary adenylate cyclase‐activating peptide promote axonal sprouting of primary afferent and cranial motor neurones

“…Specific receptor antagonists that block the sprouting response need to be developed. The peptidergic galanin antagonist M35 [galanin(1-13)-bradykinin (2-9)amide] is apparently not suitable for antagonizing galanin effects in vitro or in vivo because M35 is acting as a partial agonist at a higher dose (Ogren et al, 1993;Kask et al, 1995;Mahoney et al, 2003b).…”

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

“…Together these results suggest GAL 1 is not responsible for the proregenerative effects of galanin. Furthermore, the deficits in neurite outgrowth of neurons from the galanin-KO mouse can be rescued by addition of the GAL 2/3 specific agonist galanin (2-11) (Mahoney et al, 2003b), suggesting GAL 2 mediates the neuritogenic effects of galanin. This is confirmed by the finding that GAL 2 -KO mice have a one-third reduction in neurite outgrowth consistent with that observed in galanin-KO mice (Hobson et al, 2006), which cannot be rescued by the addition of galanin or galanin (2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”