Fatty-acid-binding protein inhibition produces analgesic effects through peripheral and central mechanisms.
Background Fatty-acid-binding proteins (FABPs) are intracellular carriers for endocannabinoids, N-acylethanolamines, and related lipids. Previous work indicates that systemically administered FABP5 inhibitors produce analgesia in models of inflammatory pain. It is currently not known whether FABP inhibitors exert their effects through peripheral or central mechanisms. Here, we examined FABP5 distribution in dorsal root ganglia and spinal cord and examined the analgesic effects of peripherally and centrally administered FABP5 inhibitors. Results Immunofluorescence revealed robust expression of FABP5 in lumbar dorsal root ganglia. FABP5 was distributed in peptidergic calcitonin gene-related peptide-expressing dorsal root ganglia and non-peptidergic isolectin B4-expressing dorsal root ganglia. In addition, the majority of dorsal root ganglia expressing FABP5 also expressed transient receptor potential vanilloid 1 (TRPV1) and peripherin, a marker of nociceptive fibers. Intraplantar administration of FABP5 inhibitors reduced thermal and mechanical hyperalgesia in the complete Freund's adjuvant model of chronic inflammatory pain. In contrast to its robust expression in dorsal root ganglia, FABP5 was sparsely distributed in the lumbar spinal cord and intrathecal administration of FABP inhibitor did not confer analgesic effects. Administration of FABP inhibitor via the intracerebroventricular (i.c.v.) route reduced thermal hyperalgesia. Antagonists of peroxisome proliferator-activated receptor alpha blocked the analgesic effects of peripherally and i.c.v. administered FABP inhibitor while antagonism of cannabinoid receptor 1 blocked the effects of peripheral FABP inhibition and a TRPV1 antagonist blocked the effects of i.c.v. administered inhibitor. Although FABP5 and TRPV1 were co-expressed in the periaqueductal gray region of the brain, which is known to modulate pain, knockdown of FABP5 in the periaqueductal gray using adeno-associated viruses and pharmacological FABP5 inhibition did not produce analgesic effects. Conclusions This study demonstrates that FABP5 is highly expressed in nociceptive dorsal root ganglia neurons and FABP inhibitors exert peripheral and supraspinal analgesic effects. This indicates that peripherally restricted FABP inhibitors may serve as a new class of analgesic and anti-inflammatory agents.
1 Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA.
Xiaoxue
X
Peng
1 Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA.
Keith
K
Studholme
1 Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA.
Martha P
MP
Kanjiya
1 Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA.
Jennifer
J
Luk
1 Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA.
Diane
D
Bogdan
2 Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.
Matthew W
MW
Elmes
2 Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.
Gregory
G
Carbonetti
3 Department of Chemistry, Stony Brook University, Stony Brook, NY, USA.|4 Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.
Simon
S
Tong
3 Department of Chemistry, Stony Brook University, Stony Brook, NY, USA.|4 Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.
Yu-Han
YH
Gary Teng
4 Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.|5 Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA.
Robert C
RC
Rizzo
2 Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.|4 Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.
Huilin
H
Li
2 Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.|4 Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.
Dale G
DG
Deutsch
3 Department of Chemistry, Stony Brook University, Stony Brook, NY, USA.|4 Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.
Iwao
I
Ojima
1 Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA.
Mario J
MJ
Rebecchi
1 Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA.
Michelino
M
Puopolo
1 Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA.|2 Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.|4 Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.
Martin
M
Kaczocha
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D003503:Cyclobutanes / Q000627:therapeutic use; D003998:Dicarboxylic Acids / Q000627:therapeutic use; D004195:Disease Models, Animal; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005620:Freund's Adjuvant / Q000633:toxicity; D005727:Ganglia, Spinal / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000150:complications / Q000188:drug therapy* / Q000209:etiology; D017288:Pain Threshold / Q000187:drug effects; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
C000621416:1-naphthyl alpha-truxillate; D000700:Analgesics; D001095:Arachidonic Acids; D003503:Cyclobutanes; D003998:Dicarboxylic Acids; C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D005620:Freund's Adjuvant
Fatty-acid-binding protein; anandamide; endocannabinoid; pain