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J Pain. 2012 Sep;13(9):836-48. doi: 10.1016/j.jpain.2012.05.013. Epub 2012 Aug 14.

Spinal cannabinoid receptor type 2 agonist reduces mechanical allodynia and induces mitogen-activated protein kinase phosphatases in a rat model of neuropathic pain.

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Dartmouth Medical School, Department of Anesthesiology, Lebanon, New Hampshire, USA.


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.


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.

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