Inhibiting Spinal Neuron-Astrocytic Activation Correlates with Synergistic Analgesia of Dexmedetomidine and Ropivacaine

Wu, Huang-Hui; Yin, Jun-Bin; Zhang, Ting; Cui, Yuanyuan; Dong, Yu-Lin; Chen, Guozhong; Wang, Wen

doi:10.1371/journal.pone.0092374

Cited by 19 publications

(20 citation statements)

References 61 publications

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“…However, its relative neurotoxicity limits the clinical use. Accumulative evidence indicates that Ropi is considered as an effective drug in many kinds of pain models, such as CFA-induced chronic inflammatory pain and neuropathic pain (14,29). The analgesic effect of Ropi is contributed to inhibition of the overexpression of spinal c-Fos and GFAP in neuropathic pain that is consistent with previous electrophysiological results.…”

Section: Discussionsupporting

confidence: 87%

“…Based on the following evidence, we suggested thay combination of MZL&Ropi might induce synergistic analgesia. First, Ropi as a block of fast voltage-gated sodium channels on neuronal axons is used as analgesia for many kinds of pain in basic experiments (13,14) and clinical trials (15,16). In our previous study, Ropi c alleviated CFA-induced chronic inflammatory pain in rats, and combination with Ropi and Dex showed synergistic analgesia on the chronic inflammatory pain (14).…”

Section: Midazolam and Ropivacaine Act Synergistically To Inhibit Bonmentioning

confidence: 99%

“…First, Ropi as a block of fast voltage-gated sodium channels on neuronal axons is used as analgesia for many kinds of pain in basic experiments (13,14) and clinical trials (15,16). In our previous study, Ropi c alleviated CFA-induced chronic inflammatory pain in rats, and combination with Ropi and Dex showed synergistic analgesia on the chronic inflammatory pain (14). Second, the increased expression of peripheral-type benzodiazepine receptors (PBRs, also named translocator protein, TSPO) are detected in astrocytes and microglia in inflammatory or nerve injury models (17,18).…”

Section: Midazolam and Ropivacaine Act Synergistically To Inhibit Bonmentioning

confidence: 99%

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

Guo

Bai

et al. 2016

Oncology Reports

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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.

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Section: Discussionsupporting

confidence: 87%

Section: Midazolam and Ropivacaine Act Synergistically To Inhibit Bonmentioning

confidence: 99%

Section: Midazolam and Ropivacaine Act Synergistically To Inhibit Bonmentioning

confidence: 99%

See 1 more Smart Citation

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

Guo

Bai

et al. 2016

Oncology Reports

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“…The minimal force that caused lifting or licking responses at least five times was considered as the PWT. Thermal hyperalgesia was tested by the Hargreaves method (Hargreaves et al, 1988; Wu et al, 2014). The infrared heat was applied to the hind plantar surface to induce paw withdrawal.…”

Section: Methodsmentioning

confidence: 99%

Endomorphin-2 Inhibition of Substance P Signaling within Lamina I of the Spinal Cord Is Impaired in Diabetic Neuropathic Pain Rats

Wan

Bai

Kou

et al. 2017

Front. Mol. Neurosci.

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Opiate analgesia in the spinal cord is impaired in diabetic neuropathic pain (DNP), but until now the reason is unknown. We hypothesized that it resulted from a decreased inhibition of substance P (SP) signaling within the dorsal horn of the spinal cord. To investigate this possibility, we evaluated the effects of endomorphin-2 (EM2), an endogenous ligand of the μ-opioid receptor (MOR), on SP release within lamina I of the spinal dorsal horn (SDH) in rats with DNP. We established the DNP rat model and compared the analgesic efficacy of EM2 between inflammation pain and DNP rat models. Behavioral results suggested that the analgesic efficacy of EM2 was compromised in the condition of painful diabetic neuropathy. Then, we measured presynaptic SP release induced by different stimulating modalities via neurokinin-1 receptor (NK1R) internalization. Although there was no significant change in basal and evoked SP release between control and DNP rats, EM2 failed to inhibit SP release by noxious mechanical and thermal stimuli in DNP but not in control and inflammation pain model. We also observed that EM2 decreased the number of FOS-positive neurons within lamina I of the SDH but did not change the amount of FOS/NK1R double-labeled neurons. Finally, we identified a remarkable decrease in MORs within the primary afferent fibers and dorsal root ganglion (DRG) neurons by Western blot (WB) and immunohistochemistry (IHC). Taken together, these data suggest that reduced presynaptic MOR expression might account for the loss of the inhibitory effect of EM2 on SP signaling, which might be one of the neurobiological foundations for decreased opioid efficacy in the treatment of DNP.

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“…Preclinical studies have typically shown minimal effects upon acute nociception at sub-motor impairing doses of conventional sodium channel blockers given intrathecally. However, they are reported to reliably result in a remarkable analgesic synergy with intrathecal agents such as opiates or alpha 2 agonists with minimal attendant effects upon motor function in animal models [111][112][113][114] and in humans [115][116][117]. There is a clinical literature that suggests that neuraxial local anesthetics may display a tachyphylaxis with chronic exposure that may respond to different local anesthetics [118].…”

Section: Spinal Antagonistsmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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Inhibiting Spinal Neuron-Astrocytic Activation Correlates with Synergistic Analgesia of Dexmedetomidine and Ropivacaine

Cited by 19 publications

References 61 publications

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

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

Endomorphin-2 Inhibition of Substance P Signaling within Lamina I of the Spinal Cord Is Impaired in Diabetic Neuropathic Pain Rats

Current and Future Issues in the development of spinal agents for the management of pain

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