Abstract
BackgroundThis study aims to identify that intrathecal (i.t.) injection of dexmedetomidine (Dex) and ropivacaine (Ropi) induces synergistic analgesia on chronic inflammatory pain and is accompanied with corresponding “neuron-astrocytic” alterations.MethodsMale, adult Sprague-Dawley rats were randomly divided into sham, control and i.t. medication groups. The analgesia profiles of i.t. Dex, Ropi, and their combination detected by Hargreaves heat test were investigated on the subcutaneous (s.c.) injection of complete Freund adjuvant (CFA) induced chronic pain in rat and their synergistic analgesia was confirmed by using isobolographic analysis. During consecutive daily administration, pain behavior was daily recorded, and immunohistochemical staining was applied to investigate the number of Fos-immunoreactive (Fos-ir) neurons on hour 2 and day 1, 3 and 7, and the expression of glial fibrillary acidic protein (GFAP) within the spinal dorsal horn (SDH) on day 1, 3, 5 and 7 after s.c. injection of CFA, respectively, and then Western blot to examine spinal GFAP and β-actin levels on day 3 and 7.Resultsi.t. Dex or Ropi displayed a short-term analgesia in a dose-dependent manner, and consecutive daily administrations of their combination showed synergistic analgesia and remarkably down-regulated neuronal and astrocytic activations indicated by decreases in the number of Fos-ir neurons and the GFAP expression within the SDH, respectively.Conclusioni.t. co-delivery of Dex and Ropi shows synergistic analgesia on the chronic inflammatory pain, in which spinal “neuron-astrocytic activation” mechanism may play an important role.
Highlights
Analgesia with local anesthetics (LAs) has been proved to be effective in neuraxial block [1,2,3,4,5]
Animal preparation Male Sprague-Dawley (SD) rats (180–220 g) provided by Experimental Animal Center of the Fourth Military Medical University were housed in standard transparent plastic cages with a 12/12 h light/dark cycle under 22–25uC ambient temperature with food and water available
Isobolographic analysis of Dex and Ropi concomitant effect in nociceptive test showed the ED50comb was smaller than the lower (95%) range of ED50add, suggesting that the interaction between the two drugs was synergistic (Figure 3B). These results revealed that the synergistic analgesia facilitated to prolong analgesic duration and to enhance analgesic intensity with less dose of Dex and Ropi
Summary
Analgesia with local anesthetics (LAs) has been proved to be effective in neuraxial block [1,2,3,4,5]. The catastrophic neural complications [6] and great impacts on motor function restrict the intrathecal (i.t.) application [7,8]. Ropivacaine (Ropi) achieves less impact on motor function in a low concentration and favorable safety profile compared with other LAs. repeated i.t. Ropi dose-dependently induces neurotoxicity and triggers neuronal apoptosis [9,10,11]. Physicians tend to prefer the ‘‘combination analgesia’’ with low dose of Ropi and another adjuvant that employs different but somehow overlapped mechanism, may lead to the synergistic analgesia, via enhancing the shared pathways or complementing the independent pathways. This study aims to identify that intrathecal (i.t.) injection of dexmedetomidine (Dex) and ropivacaine (Ropi) induces synergistic analgesia on chronic inflammatory pain and is accompanied with corresponding ‘‘neuron-astrocytic’’ alterations
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