Cytokine involvement in dynorphin-induced allodynia.
Dynorphin A is an endogenous opioid peptide, which has previously been shown to produce a long-lasting allodynia and hyperalgesia in mice, behavioral states consistent with signs of clinically observed neuropathic pain. This dynorphin-induced allodynia was used as a pharmacological, central model of neuropathic pain. In this study, we examined the involvement of the cytokine IL-1beta, the transcription factor nuclear factor kappa B (NF-kappaB), and de novo protein synthesis in the development of allodynia induced by intrathecal (i.t.) administration of dynorphin in male ICR mice. Pretreatment with the protein synthesis inhibitor cycloheximide (0. 3-85nmol), the NF-kappaB inhibitor pyrrolidinedithiocarbamate (PDTC) (0.001-1000pmol), the IL-1 receptor antagonist (IL-1ra) protein (0. 01-100ng), the caspase-1 inhibitor (YVAD) (0.1-300pmol), and the anti-inflammatory cytokine IL-10 (0.1-300ng) all dose-dependently reduced the induction of dynorphin-induced allodynia. Finally, IL-10 administered within the first 24h after the dynorphin insult prevented the development of chronic allodynia. These results demonstrate that the anti-inflammatory cytokines IL-10 and IL-1ra impede the development of dynorphin-induced allodynia. These results also suggest that production of new proteins through NF-kappaB activation is required for the induction of allodynia. We speculate that IL-1ra, IL-10, PDTC and cycloheximide interfere with the central pro-inflammatory cascade. Modulation of cytokine activity in the spinal cord may therefore prove to be an effective therapeutic strategy for the treatment of chronic pain.
Laughlin
T M
TM
Department of Pharmacology, University of Minnesota, Minneapolis 55455, USA.
Bethea
J R
JR
Yezierski
R P
RP
Wilcox
G L
GL
D000818:Animals; D016207:Cytokines / Q000502:physiology*; D004399:Dynorphins; D006941:Hyperesthesia / Q000139:chemically induced* / Q000503:physiopathology*; D007375:Interleukin-1 / Q000502:physiology; D016753:Interleukin-10 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000502:physiology; D014176:Protein Biosynthesis
D016207:Cytokines; D007375:Interleukin-1; D016328:NF-kappa B; D016753:Interleukin-10; D004399:Dynorphins