Galanin and its receptors: a novel strategy for appetite control and obesity therapy.

The 29 amino acid neuropeptide galanin is widely distributed in the nervous and endocrine systems; highest levels of galanin synthesis and storage occur within the hypothalamus in the median eminence, but it is also abundantly expressed in the basal forebrain, the peripheral nervous system, and gut. To further define the role played by galanin in the peripheral nervous and endocrine systems, a mouse strain carrying a loss-of-function germ-line mutation of the galanin locus, engineered by targeted mutagenesis in embryonic stem cells, has been generated. The mutation removes the first five exons containing the entire coding region for the galanin peptide. Germ-line transmission of the disrupted galanin locus has been obtained, and the mutation has been bred to homozygosity on the inbred 129O1aHsd background. Phenotypic analysis of mice lacking a functional galanin gene demonstrate that these animals are viable, grow normally, and can reproduce. A marked reduction in both the anterior pituitary prolactin content and in circulating plasma levels of the hormone is evident. Lactation is abolished along with abrogation of the proliferative response of the lactotroph to estrogen. The responses of sensory neurons to injury in the mutants are markedly impaired. Peripheral nerve regeneration is reduced with associated long-term functional deficits. There is a striking reduction in the development of chronic neuropathic pain. These two phenotypic changes may be explained, in part, by the observation that a subset of dorsal root ganglion neurons is lost in the mutant animals, implying a role for galanin as a trophic cell survival factor. These initial findings have important implications for our understanding and potential therapeutic treatment of (a) sensory nerve regeneration and neuropathic pain and (b) disordered pituitary proliferation and the development of prolactinoma.

Targeted Disruption of the Murine Galanin Gene a

We investigated the peripheral function of galanin (GAL) in capsaicin (CAP)-induced inflammatory pain. Intraplantar GAL (0.1 ng/μl) alone does not produce nociceptive behaviors. However, ipsilateral but not contralateral GAL at low doses (0.1 ng/μl) significantly increases CAP-evoked nociceptive behaviors approximately twofold. This effect is attributed to activation of peripheral GAL receptor 2 (GalR2) because a selective GalR2 agonist (AR-M1896) mimics the pro-nociceptive actions of GAL. Recording from nociceptors confirms that GAL does not modify activity of nociceptors but markedly enhances CAP-induced excitation of these fibers. CAP produces a discharge rate of 0.15±0.05 impulses/s which increases to 0.54±0.17 impulses/s following CAP+GAL. Immunohistochemical studies indicate GalR2 are highly expressed (65.8%) in L5 dorsal root ganglion (DRG) cells. Also, 44.5% GalR2-positive DRG neurons label for the capsaicin receptor (vanilloid receptor 1, VR1) while 61.7% of VR1-positive DRG neurons label for GalR2; 28.1% of total DRG neurons are double-labeled supporting the hypothesis that GAL-induced effects are mediated by GalR2 on capsaicin-sensitive primary afferents. Furthermore, 68.0% unmyelinated and 23.1% myelinated digital nerve axons label for GalR2, indicating the receptor is transported out to the periphery. Immunostaining for GAL peptide in digital nerves labels 46.4% unmyelinated and 27.1% myelinated axons, suggesting that afferents are a major source of ligand for peripheral GalR2. These results suggest that peripheral GAL has an excitatory role in inflammatory pain, likely mediated by peripheral GalR2 and that GAL can modulate VR1 function.

Pro-nociceptive role of peripheral galanin in inflammatory pain

The neuropeptide galanin has been reported to have a wide range of biological actions both in the central nervous system and in the gastrointestinal tract. Recent works led to the discovery of selective galanin receptor antagonists including M15 (galanin 1-12 -Pro-substanceP 5-11 -amide), M35 (galanin 1-12 -Pro-bradykinin 2-9 -amide) and C7 (galanin 1-12 -Pro-spantide-amide). These antagonists were shown to competitively inhibit actions of galanin in the central nervous system. The present study was designed to investigate the effect of galanin, M15, M35 and C7 on gastric acid secretion and gastric emptying. Pentagastrin-stimulated gastric acid secretion was inhibited by galanin (0.1–9 nmol.kg –1 .h –1 , i.v.) in a dose-dependent manner (ID 50  = 1.8 ± 0.3 nmol.kg –1 .h –1 ). When 9 nmol.kg –1 .h –1 galanin infusion was given, inhibition became almost complete. M15, M35 and C7 (1–9 nmol.kg –1 .h –1 ) did not modify responses of the stomach to galanin, but acted as agonists of galanin on acid secretion. Neither galanin nor its putative antagonists affected the emptying of non-caloric liquids from the stomach. In conclusion, galanin may play an antisecretory role in the regulation of gastric acid secretion but not in the control of gastric emptying of liquids in rats. Its antisecretory action on the stomach is mediated by galanin receptors that are distinct from those in the central nervous system.

Szczurowicz A

Papers

Galanin, galantide and galanin (1-14)-[alpha-aminobutyric acid8]-scyliorhinin-I: structure dependent effects on the rat isolated gastric fundus.

Contractile action of galanin analogues on rat isolated gastric fundus strips is modified by tachyphylaxis to substance p