Receptor subtype-specific pronociceptive and analgesic actions of galanin in the spinal cord: selective actions via GalR1 and GalR2 receptors.
Galanin is a 29-aa neuropeptide with a complex role in pain processing. Several galanin receptor subtypes are present in dorsal root ganglia and spinal cord with a differential distribution. Here, we describe a generation of a specific galanin R2 (GalR2) agonist, AR-M1896, and its application in studies of a rat neuropathic pain model (Bennett). The results show that in normal rats mechanical and cold allodynia of the hindpaw are induced after intrathecal infusion of low-dose galanin (25 ng per 0.5 microl/h). The same effect is seen with equimolar doses of AR-M1896 or AR-M961, an agonist both at GalR1 and GalR2 receptors. In allodynic Bennett model rats, the mechanical threshold increased dose-dependently after intrathecal injection of a high dose of AR-M961, whereas no effect was observed in the control or AR-M1896 group. No effect of either of the two compounds was observed in nonallodynic Bennett model rats. These data indicate that a low dose of galanin has a nociceptive role at the spinal cord level mediated by GalR2 receptors, whereas the antiallodynic effect of high-dose galanin on neuropathic pain is mediated by the GalR1 receptors. Thus, a selective GalR1 agonist may be used to treat neuropathic pain.
Liu
H X
HX
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Brumovsky
P
P
Schmidt
R
R
Brown
W
W
Payza
K
K
Hodzic
L
L
Pou
C
C
Godbout
C
C
Hökfelt
T
T
D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002422:Causalgia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D003080:Cold Temperature / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D019004:Galanin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology* / Q000627:therapeutic use / Q000633:toxicity; D005727:Ganglia, Spinal / Q000737:chemistry / Q000187:drug effects; D006614:Hindlimb / Q000294:innervation; D006941:Hyperesthesia / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D015918:Infusion Pumps, Implantable; D008297:Male; D023421:Models, Animal; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000502:physiology*; D017288:Pain Threshold / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D020033:Protein Isoforms / Q000819:agonists / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044088:Receptors, Galanin; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000502:physiology*; D012584:Sciatic Nerve / Q000293:injuries; D012585:Sciatica / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D013116:Spinal Cord / Q000737:chemistry / Q000503:physiopathology*; D013314:Stress, Mechanical; D013379:Substrate Specificity
D018712:Analgesics, Non-Narcotic; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; D044088:Receptors, Galanin; D018013:Receptors, Neuropeptide; C434735:galanin (1-11)-amide; C434733:galanin (1-16)-amide, Sar(1)-Ala(12)-; C434734:galanin (2-11)-amide; D019004:Galanin