Midazolam and ropivacaine act synergistically to inhibit bone cancer pain with different mechanisms in rats

Abstract

Analgesic strategy of a single drug analgesia in bone cancer pain (BCP) has shifted to combined analgesia with different drugs which have different mechanism. After tumor cell inculation, the activation of signal transducer and activator of transcription (STAT3) and extracellular signal-regulated kinase (ERK) signaling pathway are involved in the development and maintenance of BCP, whereas a decrease in the expression of spinal STAT3 and ERK through using their specific blocker, lead to attenuation of BCP. Hence, in this study, we clarified that intrathecal (i.t.) injection of midazolam (MZL) and ropivacaine (Ropi) induces synergistic analgesia on BCP and is accompanied with different mechanisms of these analgesic effect. Hargreaves heat test was used to detect the analgesic effect of single dose of i.t. MZL, Ropi and their combination on the BCP rats. At consecutive daily administration experiment, thermal hyperalgesia was recorded, and immunohistochemical staining was used to detect the expression of c-Fos, spinal glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule-1 (IBA-1). Then, western blot analysis was used to examine spinal TSPO, GFAP, IBA-1, pERK/ERK and pSTAT3/STAT3 levels on day 14 after tumor cell inoculation. i.t. MZL or Ropi showed a short-term analgesia dose-dependently, and MZL displayed better effect on inhibition of pSTAT3 expression than pERK, but Ropi was just the reverse, then consecutive daily administrations of their combination acted synergistically to attenuate thermal hyperalgesia with downregulated spinal 'neuron-astrocytic activation' in the BCP rats. i.t. co-delivery of MZL and Ropi shows synergistic analgesia on the BCP with the inhibition of spinal 'neuron-astrocytic activation'. Spinal different signaling pathway inhibition for MZL and Ropi may be involved in this process.

<p>Ropivacaine Inhibits the Growth, Migration and Invasion of Gastric Cancer Through Attenuation of WEE1 and PI3K/AKT Signaling via miR-520a-3p</p>

“…21 On the other hand, studies have confirmed that midazolam and Rop synergistically inhibit bone cancer pain in rats with different mechanisms. 22 Moreover, Rop also plays an important role in tumors. For example, Rop regulates CD62E expression and reduces tumor cell arrest through NF-κB signaling pathway.…”

B14 ameliorates bone cancer pain through downregulating spinal interleukin-1β via suppressing neuron JAK2/STAT3 pathway

“…47 The variation tendency of p-JAK2/ JAK2 ratio and p-STAT3/STAT3 ratio was similar to that of our previous research, which was increased from days 12 to 18. 48,49 IL-1b is a downstream inflammatory factor of JAK3/STAT3 signaling pathway. 29 Former research papers reported that IL-1b has the ability to act as a neurotoxic mediator, 30 while few others demonstrated that IL-1b mediated neuronal apoptosis via p-38 mitogen-activated protein kinase activity after spinal cord injury.…”

Translocator Protein 18 kDa (TSPO) as a Novel Therapeutic Target for Chronic Pain

“…Herein, we focus on the anti-inflammation effects of TSPO in chronic pain from bone metastasis. TSPO level is increased in both astrocytes and microglia of a rat model for bone cancer pain (BCP) [ 26 ]. Further, a single intrathecal administration of midazolam (MZL), an agonistic TSPO ligand [ 38 ], can inhibit thermal hyperalgesia in BCP rats via spinal activation of TSPO.…”

“…IL-6 is considered a trigger for the initiation and maintenance of chronic pain [ 38 ]. In the BCP model, IL-6 expression increased in the DRG and spinal cord [ 26 , 39 ]. Remarkably, Fang et al attenuated bone cancer-induced hyperalgesia in BCP rats by inhibiting the IL-6/sIL-6R trans-signaling pathway, implicating IL-6 in the development of BCP [ 39 ].…”

“…These studies highlight the potential uses of TSPO and its ligands for neuroprotection, limiting neuroinflammation, promoting regeneration, and treating nervous system dysfunctions. Herein, we review the current evidence for the role of TSPO and its ligands in the development of chronic pain, including neuropathic pain, cancer pain, and inflammatory pain (Table 1) [24][25][26].…”