Pro-nociceptive role of peripheral galanin in inflammatory pain.
We investigated the peripheral function of galanin (GAL) in capsaicin (CAP)-induced inflammatory pain. Intraplantar GAL (0.1 ng/microl) alone does not produce nociceptive behaviors. However, ipsilateral but not contralateral GAL at low doses (0.1 ng/microl) 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.
Seccion Externa de Farmacologia, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Mexico, D.F. Mexico.
Juan Miguel
JM
Jimenez-Andrade
Shengtai
S
Zhou
Junhui
J
Du
Ammar
A
Yamani
James J
JJ
Grady
Gilberto
G
Castañeda-Hernandez
Susan M
SM
Carlton
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D001522:Behavior, Animal; D002211:Capsaicin; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019004:Galanin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008854:Microscopy, Electron / Q000379:methods; D010146:Pain / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D010525:Peripheral Nerves / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D044092:Receptor, Galanin, Type 2 / Q000819:agonists / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism; D012867:Skin / Q000294:innervation / Q000503:physiopathology; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology
D010446:Peptide Fragments; D044092:Receptor, Galanin, Type 2; D011955:Receptors, Drug; C434734:galanin (2-11)-amide; C074975:galantide; D013373:Substance P; D019004:Galanin; D002211:Capsaicin