Transient decrease in nociceptor GRK2 expression produces long-term enhancement in inflammatory pain.
In heterozygous mice, attenuation of G-protein-coupled receptor kinase 2 (GRK2) level in nociceptors is associated with enhanced and prolonged inflammatory hyperalgesia. To further elucidate the role of GRK2 in nociceptor function we reversibly decreased GRK2 expression using intrathecal antisense oligodeoxynucleotide (AS-ODN). GRK2 AS-ODN administration led to an enhanced and prolonged hyperalgesia induced by prostaglandin E(2), epinephrine and carrageenan. Moreover, this effect persisted unattenuated 2weeks after the last dose of antisense, well after GRK2 protein recovered, suggesting that transient attenuation of GRK2 produced neuroplastic changes in nociceptor function. Unlike hyperalgesic priming induced by transient activation of protein kinase C epsilon (PKCε), (Aley et al., 2000; Parada et al., 2003b), the enhanced and prolonged hyperalgesia following attenuation of GRK2 is PKCε- and cytoplasmic polyadenylation element binding protein (CPEB)-independent and is protein kinase A (PKA)- and Src tyrosine kinase (Src)-dependent. Finally, rats treated with GRK2 AS-ODN exhibited enhanced and prolonged hyperalgesia induced by direct activation of second messengers, adenyl cyclase, Epac or PKA, suggesting changes downstream of G-protein-coupled receptors. Because inflammation can produce a decrease in GRK2, such a mechanism could help explain a predilection to develop chronic pain, after resolution of acute inflammation.
Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA.
L F
LF
Ferrari
O
O
Bogen
N
N
Alessandri-Haber
E
E
Levine
R W
RW
Gear
J D
JD
Levine
D000818:Animals; D015153:Blotting, Western; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000096:biosynthesis / Q000235:genetics*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006930:Hyperalgesia / Q000235:genetics / Q000523:psychology; D007249:Inflammation / Q000150:complications / Q000235:genetics*; D008297:Male; D009619:Nociceptors / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010146:Pain / Q000209:etiology / Q000235:genetics*; D017288:Pain Threshold; D054799:Phospholipase C beta / Q000096:biosynthesis / Q000235:genetics; D051744:Protein Kinase C-epsilon / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000502:physiology
C539243:CPEB1 protein, rat; D020319:Oligodeoxyribonucleotides, Antisense; D016601:RNA-Binding Proteins; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D051744:Protein Kinase C-epsilon; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2; D054799:Phospholipase C beta