Combination of Tramadol with Minocycline Exerted Synergistic Effects on a Rat Model of Nerve Injury-Induced Neuropathic Pain

Abstract

Neuropathic pain is a refractory clinical problem. Certain drugs, such as tramadol, proved useful for the treatment of neuropathic pain by inhibiting the activity of nociceptive neurons. Moreover, studies indicated that suppression or modulation of glial activation could prevent or reverse neuropathic pain, for example with the microglia inhibitor minocycline. However, few present clinical therapeutics focused on both neuronal and glial participation when treating neuropathic pain. Therefore, the present study hypothesized that combination of tramadol with minocycline as neuronal and glial activation inhibitor may exert some synergistic effects on spinal nerve ligation (SNL)-induced neuropathic pain. Intrathecal tramadol or minocycline relieved SNL-induced mechanical allodynia in a dose-dependent manner. SNL-induced spinal dorsal horn Fos or OX42 expression was downregulated by intrathecal tramadol or minocycline. Combination of tramadol with minocycline exerted powerful and synergistic effects on SNL-induced neuropathic pain also in a dose-dependent manner. Moreover, the drug combination enhanced the suppression effects on SNL-induced spinal dorsal horn Fos and OX42 expression, compared to either drug administered alone. These results indicated that combination of tramadol with minocycline could exert synergistic effects on peripheral nerve injury-induced neuropathic pain; thus, a new strategy for treating neuropathic pain by breaking the interaction between neurons and glia bilaterally was also proposed.

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

“…It has been observed in our previous report that coadministration of tramadol and minocycline indicated synergistic effects on peripheral nerve injury-induced neuropathic pain [13]. Consequently, the present study suggests that suppressing peripheral nerve injury-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 peripheral nerve injury-induced neuropathic pain.…”

“…Normal saline (0.9%) was used as the negative control. The dose for intrathecal administration (tramadol 10 μg/rat, minocycline 30 μg/rat or combination tramadol 3.9 μg/rat + minocycline 27.3 μg/rat) was based on our previous study [13]. …”

“…Our previous report [13] has suggested that coadministration of tramadol and minocycline exerted synergistic effects on peripheral nerve injury-induced neuropathic pain. However, the underlying mechanisms are unclear.…”

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

“…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). 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).…”

The Antinociceptive Effects of Tramadol and/or Gabapentin on Rat Neuropathic Pain Induced by a Chronic Constriction Injury

“…Tra has been combined with other drugs, e.g., dexmedetomidine [Farghaly et al, ], propentofylline [Zhang et al, ], minocycline [Mei et al, ], doxepin [Uyar et al, ], dexmedetomidine [Guneli et al, ] to generate synergistic interactions. Tra and venlafaxine in combination are additive in producing antihyperalgesic and anti‐allodynic effects [Uyar et al, ; Wrzosek et al, ].…”