Abstract
Peripheral nerve injury generally results in spinal neuronal and glial plastic changes
associated with chronic behavioral hypersensitivity. Spinal mitogen-activated protein
kinases (MAPKs), eg, p38 or extracellular signal-regulated kinases (ERKs), are instrumental
in the development of chronic allodynia in rodents, and new p38 inhibitors have shown
potential in acute and neuropathic pain patients. We have previously shown that the
cannabinoid type 2 receptor agonist JWH015 inhibits ERK activity by inducing MAPK
phosphatase (MKP)-1 and MKP-3 (the major regulators of MAPKs) in vitro in microglial
cells. Therefore, we decided to investigate the role of these phosphatases in the
mechanisms of action of JWH015 in vivo using the rat L5 nerve transection model of
neuropathic pain. We observed that peripheral nerve injury reduced spinal MKP-1/3
expression and activity and that intrathecal JWH015 reduced established L5 nerve injury-induced
allodynia, enhanced spinal MKP-1/3 expression and activity, and reduced the phosphorylated
form of p38 and ERK-1/2. Triptolide, a pharmacological blocker of MKP-1 and MKP-3
expression, inhibited JWH015’s effects, suggesting that JWH015 exerts its antinociceptive
effects by modulating MKP-1 and MKP-3. JWH015-induced antinociception and MKP-1 and
MKP-3 expression were inhibited by the cannabinoid type 2 receptor antagonist AM630.
Our data suggest that MKP-1 and MKP-3 are potential targets for novel analgesic drugs.
Perspective
MAPKs are pivotal in the development of chronic allodynia in rodent models of neuropathic
pain. A cannabinoid type 2 receptor agonist, JWH015, reduced neuropathic allodynia
in rats by reducing MAPK phosphorylation and inducing spinal MAPK phosphatases 1 and
3, the major regulators of MAPKs.
Key words
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Article info
Publication history
Published online: August 16, 2012
Accepted:
May 10,
2012
Received in revised form:
May 7,
2012
Received:
February 28,
2012
Footnotes
Supported by the American Pain Society 2008 Future Leaders in Pain Research Small Grants, the Rita Allen Foundation & American Pain Society 2011 Pain grant (E.A.R.-S.), Hitchcock Foundation award 2011-2012, and the National Institute of Drug Abuse DA025211 (E.A.R.-S.) and DA11276 (J.A.D).
The authors declare no conflict of interest.
Identification
Copyright
© 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.
