Abstract
Nociceptin/orphanin FQ (N/OFQ) antinociception, which is mediated selectively by the N/OFQ peptide receptor (NOP), was demonstrated in pain models. In this study, we determine the role of activated microglia on the analgesic effects of N/OFQ in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. Repeated 7-day administration of minocycline (30 mg/kg i.p.), a drug that affects microglial activation, significantly reduced pain in CCI-exposed rats and it potentiates the analgesic effects of administered N/OFQ (2.5–5 μg i.t.). Minocycline also downregulates the nerve injury-induced upregulation of NOP protein in the dorsal lumbar spinal cord. Our in vitro study showed that minocycline reduced NOP mRNA, but not protein, level in rat primary microglial cell cultures. In [35S]GTPγS binding assays we have shown that minocycline increases the spinal N/OFQ-stimulated NOP signaling. We suggest that the modulation of the N/OFQ system by minocycline is due to the potentiation of its neuronal antinociceptive activity and weakening of the microglial cell activation. This effect is beneficial for pain relief, and these results suggest new targets for the development of drugs that are effective against neuropathic pain.
Highlights
Neuropathic pain is a common consequence of nervous tissue damage
Minocycline potentiates the effects of Nociceptin/orphanin FQ (N/OFQ) through the downregulation of microglial activation and by decreasing the microglial pool of N/OFQ peptide receptor (NOP)
It increases the analgesic action of N/OFQ through neuronal receptors, and it potentiates the receptor-ligand signaling through the upregulation of G-protein activation
Summary
Neuropathic pain is a common consequence of nervous tissue damage. The mechanisms underlying neuropathy still remain unclear, and the currently available drugs are frequently ineffective, making treatment a major clinical challenge [1, 2]. Nociceptin/orphanin FQ (N/OFQ) acts through the N/OFQ peptide receptor (NOP) [3] and can change responsiveness to painful stimuli in several models of pain [4,5,6]. Proand antinociceptive effects of N/OFQ have been reported in a variety of animal models depending on the route of administration. Intracerebroventricular (i.c.v.) administration was found to display hyperalgesic effects [3, 7, 8], which were mediated by NOP, as these effects are not present in NOP-knockout mice [9]. N/OFQ administered intrathecally (i.t.) has been generally found to produce antinociceptive responses [4, 5, 10,11,12,13,14,15,16]
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