The Therapeutic Effect of Dexmedetomidine on Rat Diabetic Neuropathy Pain and the Mechanism

Lu, Yingshen; Lin, Bo; Zhong, Junmin

doi:10.1248/bpb.b17-00224

Cited by 21 publications

(16 citation statements)

References 26 publications

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“…Furthermore, when dexmedetomidine was administered systemically it increased pain threshold, suppressed microglia activation, and decreased pro-inflammatory cytokines in the spinal cord in streptozotocin-induced diabetic rats. 32 This finding of a protective rather detrimental effect with systemic dexmedetomidine is consistent with protective effects afforded by intravenous infusion of dexmedetomidine. 33 The dose of dexmedetomidine used in our study is much higher than that being used clinically.…”

Section: Discussionsupporting

confidence: 76%

Dexmedetomidine enhances ropivacaine-induced sciatic nerve injury in diabetic rats

Geng

et al. 2019

British Journal of Anaesthesia

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Background: Previous studies suggest that dexmedetomidine has a protective effect against local anaesthetic-induced nerve injury in regional nerve blocks. Whether this potentially protective effect exists in the context of diabetes mellitus is unknown. Methods: A diabetic state was established in adult male SpragueeDawley rats with intraperitoneal injection of streptozotocin. Injections of ropivacaine 0.5%, dexmedetomidine 20 mg kg À1 (alone and in combination), or normal saline (all in 0.2 ml) were made around the sciatic nerve in control and diabetic rats (n¼8 per group). The duration of sensory and motor nerve block and the motor nerve conduction velocity (MNCV) were determined. Sciatic nerves were harvested at post-injection day 7 and assessed with light and electron microscopy or used for pro-inflammatory cytokine measurements. Results: Ropivacaine and dexmedetomidine alone or in combination did not produce nerve fibre damage in control nondiabetic rats. In diabetic rats, ropivacaine induced significant nerve fibre damage, which was enhanced by dexmedetomidine. This manifested with slowed MNCV, decreased axon density, and decreased ratio of inner to outer diameter of the myelin sheath (G ratio). Demyelination, axon disappearance, and empty vacuoles were also found using electron microscopy. An associated increase in nerve interleukin-1b and tumour necrosis factor-a was also seen. Conclusions: Ropivacaine 0.5% causes significant sciatic nerve injury in diabetic rats that is greatly potentiated by highdose dexmedetomidine. Although the dose of dexmedetomidine used in this study is considerably higher than that used in clinical practice, our data suggest that further studies to assess ropivacaine (alone and in combination with dexmedetomidine) use for peripheral nerve blockade in diabetic patients are warranted.

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Section: Discussionsupporting

confidence: 76%

Dexmedetomidine enhances ropivacaine-induced sciatic nerve injury in diabetic rats

Geng

et al. 2019

British Journal of Anaesthesia

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“… 1 , 2 In an animal model of DNP, rats exhibited increase in levels of proinflammatory cytokines in the dorsal spinal cord – a critical region involved in the development of DNP. 3 Subsequent studies showed that changes in proinflammatory cytokines in the dorsal spinal cord are paralleled by pain behavior in DNP rats. 3 , 4 Elevated levels of spinal cord proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were observed in rats with diabetic neuropathy.…”

Section: Introductionmentioning

confidence: 99%

“… 3 Subsequent studies showed that changes in proinflammatory cytokines in the dorsal spinal cord are paralleled by pain behavior in DNP rats. 3 , 4 Elevated levels of spinal cord proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were observed in rats with diabetic neuropathy. 3 – 7 Emerging evidence recently revealed that chronic administration of minocycline – an inhibitor of microglia activation – suppressed levels of proinflammatory cytokines and attenuated mechanical allodynia in diabetic rats.…”

Section: Introductionmentioning

confidence: 99%

“… 3 , 4 Elevated levels of spinal cord proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were observed in rats with diabetic neuropathy. 3 – 7 Emerging evidence recently revealed that chronic administration of minocycline – an inhibitor of microglia activation – suppressed levels of proinflammatory cytokines and attenuated mechanical allodynia in diabetic rats. 2 , 8 Although microglial activation has been implicated in the development of DNP, there is poor understanding of the mechanism underlying microglial activation and accumulation of proinflammatory cytokines in the dorsal spinal cord of diabetic animals.…”

Section: Introductionmentioning

confidence: 99%

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Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain

Zhou

Liu

et al. 2018

JPR

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ObjectiveThe dorsal horn P2Y13 receptor is involved in the development of pain behavior induced by peripheral nerve injury. It is unclear whether the expression of proinflammatory cytokines interleukin (IL)-1β and IL-6 at the spinal dorsal horn are influenced after the activation of P2Y13 receptor in rats with diabetic neuropathic pain (DNP).MethodsA rat model of type 1 DNP was induced by intraperitoneal injection of streptozotocin (STZ). We examined the expression of P2Y13 receptor, Iba-1, IL-1β, IL-6, JAK2, STAT3, pTyr1336, and pTyr1472 NR2B in rat spinal dorsal horn.ResultsCompared with normal rats, STZ-diabetic rats displayed obvious mechanical allodynia and the increased expression of P2Y13 receptor, Iba-1, IL-1β, and IL-6 in the dorsal spinal cord that was continued for 6 weeks in DNP rats. The data obtained indicated that, in DNP rats, administration of MRS2211 significantly attenuated mechanical allodynia. Compared with DNP rats, after MRS2211 treatment, expression of the P2Y13 receptor, Iba-1, IL-1β, and IL-6 were reduced 4 weeks after the STZ injection. However, MRS2211 treatment did not attenuate the expression of the P2Y13 receptor, Iba-1, IL-1β, and IL-6 at 6 weeks after the STZ injection. MRS2211 suppressed JAK2 and STAT3 expression in the early stage, but not in the later stage. Moreover, pTyr1336 NR2B was significantly decreased, whereas pTyr1472 NR2B was unaffected in the dorsal spinal cord of MRS2211-treated DNP rats.ConclusionIntrathecal MRS2211 produces an anti-nociceptive effect in early-stage DNP. A possible mechanism involved in MRS2211-induced analgesia is that blocking the P2Y13 receptor downregulates levels of IL-1β and IL-6, which subsequently inhibit the activation of the JAK2/STAT3 signaling pathway. Furthermore, blocking the activation of the P2Y13 receptor can decrease NR2B-containing NMDAR phosphorylation in dorsal spinal cord neurons, thereby attenuating central sensitization in STZ-induced DNP rats.

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“… 17 – 20 Diabetic neuropathic pain is one of the main symptoms; however, currently available drugs are often ineffective and complicated by adverse events. 18 , 21 – 24 Neuropathic pain is a frequently encountered condition that is often resistant to treatment and is associated with poor patient satisfaction of their treatment. The management of chronic neuropathic pain is challenging 25 and is best achieved with the use of effective targets related to the main mechanisms associated with pain transduction.…”

Section: Introductionmentioning

confidence: 99%

KCNQ2/3/5 channels in dorsal root ganglion neurons can be therapeutic targets of neuropathic pain in diabetic rats

Liu

et al. 2018

Mol Pain

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BackgroundDiabetic neuropathic pain is poorly controlled by analgesics, and the precise molecular mechanisms underlying hyperalgesia remain unclear. The KCNQ2/3/5 channels expressed in dorsal root ganglion neurons are important in pain transmission. The expression and activity of KCNQ2/3/5 channels in dorsal root ganglion neurons in rats with diabetic neuropathic pain were investigated in this study.MethodsThe mRNA levels of KCNQ2/3/5 channels were analyzed by real-time polymerase chain reaction. The protein levels of KCNQ2/3/5 channels were evaluated by Western blot assay. KCNQ2/3/5 channel expression in situ in dorsal root ganglion neurons was detected by double fluorescent labeling technique. M current (IM) density and neuronal excitability were determined by whole-cell voltage and current clamp recordings. Mechanical allodynia and thermal hyperalgesia were assessed by von Frey filaments and plantar analgesia tester, respectively.ResultsThe mRNA and protein levels of KCNQ2/3/5 channels significantly decreased, followed by the reduction of IM density and elevation of neuronal excitability of dorsal root ganglion neurons from diabetic rats. Activation of KCNQ channels with retigabine reduced the hyperexcitability and inhibition of KCNQ channels with XE991 enhanced the hyperexcitability. Administration of retigabine alleviated both mechanical allodynia and thermal hyperalgesia, while XE991 augmented both mechanical allodynia and thermal hyperalgesia in diabetic neuropathic pain in rats.ConclusionThe findings elucidate the mechanisms by which downregulation of the expression and reduction of the activity of KCNQ2/3/5 channels in diabetic rat dorsal root ganglion neurons contribute to neuronal hyperexcitability, which results in hyperalgesia. These data provide intriguing evidence that activation of KCNQ2/3/5 channels might be the potential new targets for alleviating diabetic neuropathic pain symptoms.

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The Therapeutic Effect of Dexmedetomidine on Rat Diabetic Neuropathy Pain and the Mechanism

Cited by 21 publications

References 26 publications

Dexmedetomidine enhances ropivacaine-induced sciatic nerve injury in diabetic rats

Dexmedetomidine enhances ropivacaine-induced sciatic nerve injury in diabetic rats

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain

KCNQ2/3/5 channels in dorsal root ganglion neurons can be therapeutic targets of neuropathic pain in diabetic rats

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The Therapeutic Effect of Dexmedetomidine on Rat Diabetic Neuropathy Pain and the Mechanism

Cited by 21 publications

References 26 publications

Dexmedetomidine enhances ropivacaine-induced sciatic nerve injury in diabetic rats

Dexmedetomidine enhances ropivacaine-induced sciatic nerve injury in diabetic rats

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1&beta; and IL-6 in rats with diabetic neuropathic pain

KCNQ2/3/5 channels in dorsal root ganglion neurons can be therapeutic targets of neuropathic pain in diabetic rats

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Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain