Abstract
BACKGROUND AND PURPOSE:
Regulators of G protein signaling (RGS) are strong determinants of metabotropic receptor activity, reducing the lifespan of the GTP-bound state of G proteins. Accumulating evidence suggests that the reduced potency of analgesic agents in neuropathic pain may be due to alterations in RGS. We investigated the effects of intrathecal CCG 63802, a specific RGS4 inhibitor, on neuropathic pain and signaling through the cannabinoid receptor type 1 (CB1 ) after nerve lesion.
KEY RESULTS:
Male Sprague Dawley rats treated with CCG 63802 two times daily for the first week after nerve injury showed attenuated thermal hyperalgesia during the treatment period. The spinal level of anandamide was up-regulated in nerve lesioned animals irrespective of the treatment. Although the expression of CB1 was unaffected, HU210-induced CB1 signaling was impaired by the nerve lesion and rescued by intrathecal CCG 63802 treatment. A functional link between CB1 and RGS4 was unequivocally shown in transfected HEK cells combining CB1 expression with conditional expression of RGS4. Inhibition of cAMP production, a down-stream effect of CB1 signaling, was blunted upon RGS4 overexpression. RGS4 expression also attenuated the CB1 -controlled activation of extracellular-signal-regulated kinase.
CONCLUSIONS AND IMPLICATIONS:
Spinal inhibition of RGS4 restores endogenous analgesic signaling to effectively mitigate neuropathic pain. This report suggests that signaling through the CB1 may be involved in this beneficial effect. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
- PMID:
- 26478461
- [PubMed – as supplied by publisher]
