Articles: hyperalgesia.
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New therapeutics to manage post-surgical pain are needed to mitigate the liabilities of opioid and other analgesics. Our previous work shows that key modulators of excitability in peripheral nociceptors, such as extracellular signal-regulated kinases (ERK) are inhibited by activation of adenosine monophosphate activated protein kinase (AMPK). We hypothesized that AMPK activation would attenuate acute incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming caused by surgery in mice. ⋯ Finally, we used dorsal root ganglion (DRG) neurons in culture to show that resveratrol and metformin given in combination shift the concentration-response curve for AMPK activation to the left and increase the magnitude of AMPK activation. Therefore, we find that topical administration is an effective treatment route of administration and combining systemic and local treatments led to anti-nociceptive efficacy in acute mechanical hypersensitivity at doses that were not effective alone. Collectively our work demonstrates a specific effect of AMPK activators on post-surgical pain and points to novel therapeutic opportunities with potential immediate impact in the clinical setting.
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The injection of safe doses of botulinum neurotoxin A (BoNT/A) have been reported to be useful for the treatment of neuropathic pain, but it is still unknown how functional recovery is induced after peripheral nerve injury. We evaluated the effects of intranerve application of BoNT/A, on regeneration and sensorimotor functional recovery in partial and complete peripheral nerve injuries in the mouse. After sciatic nerve crush (SNC) and intranerve delivery of BoNT/A (15pg), axonal regeneration was measured by nerve pinch test at different days. ⋯ We observed also a higher expression of S100 in the distal portion of BoNT/A-injected regenerated nerves. In CCI mice, BoNT/A induced an increase in reinnervation of gastrocnemius and plantar muscles. These results show that a low dose of BoNT/A, insufficient to produce muscular dysfunction, conversely speeds up sensorimotor recovery by stimulating myelinated axonal regeneration, and points out its application as a multipotent treatment for peripheral neuropathies.
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Neuroscience letters · Sep 2017
Systemic dexmedetomidine attenuates mechanical allodynia through extracellular sign db type 2 diabetic mice.
Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus. However, the treatment for PDN is limited in clinical practice. In the present study, we investigated the effect of systemic administration dexmedetomidine (DEX), a selective alpha 2 adrenergic receptor (α2AR) agonist, on mechanical allodynia and its underlying mechanism in db/db mice, an animal model of type 2 diabetes mellitus. ⋯ Furthermore, the upregulation of pERK1 and pERK2 in db/db mice were attenuated by preadministration of dexmedetomidine. We provide the first evidence that the functional alternation of spinal noradrenergic system might underlie exaggerated nociception in PDN. Systemic dexmedetomidine inhibits the mechanical allodynia which is related to ERK signaling pathway in type 2 diabetes, implying that the α2-Adrenoceptor might be a potential therapeutic strategy for PDN.
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Diabetic neuropathy pain (DNP) is a common chronic complication of diabetes characterized by spontaneous pain, hyperalgesia and allodynia. Dexmedetomidine is a selective α2 adrenergic agonist that relieves sympathetic nervous tension and reduces the release of glutamate. Thus, it is possible that dexmedetomidine may relieve DNP as well. ⋯ Glutamate production in caudal lumbar was measured by HPLC. We found that STZ-treated rats had decreased pain threshold, elevated activation of microglia but not astrocytes, increased level of pro-inflammatory cytokines, increased apoptosis and glutamate production compared to control animals, and these effects were ameliorated by dexmedetomidine treatment. Pretreatment of yohimbine abolished almost all of the protective effects of dexmedetomidine except for glutamate production.
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The authors previously reported that noncoding microRNA miR-219-5p is down-regulated in the spinal cord in a nociceptive state. The ventral tegmental area also plays critical roles in modulating nociception, although the underlying mechanism remains unknown. The authors hypothesized that miR-219-5p in the ventral tegmental area also may modulate nociception. ⋯ Down-regulation of astroglial miR-219-5p in ventral tegmental area induced nociceptive responses are mediated by astroglial coiled-coil and C2 domain containing 1A/nuclear factor-κB signaling and elevated dopamine neuron activity.