Depressing Interleukin-1� Contributed to the Synergistic Effects of Tramadol and Minocycline on Spinal Nerve Ligation-Induced Neuropathic Pain

Abstract

Our previous study indicated that coadministration of tramadol and minocycline exerted synergistic effects on spinal nerve ligation (SNL)-induced neuropathic mechanical allodynia. However, the underlying mechanisms are still unclear. Recent reports indicated that spinal proinflammatory factor interleukin-1β (IL-1β) contributed to the development of neuropathic pain and the positive feedback communication between neuron and glia. Therefore, the present research is to confirm whether spinal IL-1β-related pathway response contributes to the synergistic effects of tramadol and minocycline on SNL-induced neuropathic pain. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn 3 days after lesion, which could be significantly decreased by tramadol and minocycline coadministration. Immunofluorescence and Western blot indicated that SNL-induced microglial phosphorylated p38 (p-p38) upregulation was also inhibited by tramadol and minocycline coapplication. Meanwhile, intrathecal administration of p38 inhibitor SB203580 markedly alleviated mechanical allodynia whilst reducing IL-1β and Fos expression induced by SNL. Moreover, intrathecal neutralized antibody of IL-1β could depress SNL-induced mechanical allodynia and Fos expression. These results suggest that depressing SNL-induced aberrant activation of the spinal dorsal horn IL-1β-related pathway contributes to the underlying mechanism of the synergistic effects of tramadol and minocycline coadministration on SNL-induced neuropathic mechanical allodynia. © 2013 S. Karger AG, Basel

Antinociceptive Interaction of Tramadol with Gabapentin in Experimental Mononeuropathic Pain

“…In this assay, gabapentin, tramadol and the combination of them were able to induce a dose-dependent antinociception, in which gabapentin was 2.29 times more potent than tramadol; results are concordant with previous reports [16][17][18].…”

IL-1 receptor antagonist improves morphine and buprenorphine efficacy in a rat neuropathic pain model

“…In our previous studies (Mika et al, 2007), we have shown that in rats and mice, minocycline (a p38 MAPK and MMP-9 inhibitor) strongly inhibits microglial activation and attenuates the development of neuropathic pain beyond what is accomplished through the potentiation of morphine analgesia. The recent study by Mei et al (2013b) indicated that under conditions of neuropathic pain, spinal IL-1beta is diminished by minocycline administration, a finding that supports our idea that IL-1beta may be one of the key factors in neuropathic pain. Interestingly, a combination of tramadol and minocycline exerted synergistic effects in a rat model of neuropathic pain (Mei et al, 2013a).…”

“…Interestingly, a combination of tramadol and minocycline exerted synergistic effects in a rat model of neuropathic pain (Mei et al, 2013a). Similarly, the administration of the p38 inhibitor SB203580 also markedly alleviated mechanical allodynia by reducing injury-induced increases in the expression of IL-1beta (Mei et al, 2013b). Pentoxifylline (a non-selective phosphodiesterase inhibitor), which is known to decrease the levels of some cytokines, including IL-1beta in rats and humans (Dorazil-Dudzik et al, 2004;Lundblad et al, 1995;Neuner et al, 1994), also significantly enhances the analgesic effects of morphine (Mika et al, 2007;.…”

Minocycline reduces mechanical allodynia and depressive-like behaviour in type-1 diabetes mellitus in the rat

“…Previous works on the effect of minocycline in non-diabetic neuropathic pain hypersensitivity suggested that the effect of treatment may depend on the time at which treatment started. Minocycline has been effective when treatment started early, before or within one to two days after the induction of non-diabetic neuropathic pain both with intrathecal [73][74][75] and systemic [27,29,[76][77][78] administrations. On the other hand, when minocycline treatment started after the establishment of non-diabetic neuropathic condition, its effect on pain behaviour, independent of the route of administration, has been poor [27,73,78].…”