Neurosteroid Allopregnanolone Suppresses Median Nerve Injury–induced Mechanical Hypersensitivity and Glial Extracellular Signal–regulated Kinase Activation through γ-Aminobutyric Acid Type A Receptor Modulation in the Rat Cuneate Nucleus

2016 ◽  
Vol 125 (6) ◽  
pp. 1202-1218 ◽  
Author(s):  
Chun-Ta Huang ◽  
Seu-Hwa Chen ◽  
June-Horng Lue ◽  
Chi-Fen Chang ◽  
Wen-Hsin Wen ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Median Nerve ◽  
Nerve Injury ◽  
Type A ◽  
Aminobutyric Acid ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Acid Type ◽  
Extracellular Signal ◽  
Median Nerve Injury

Abstract Background Mechanisms underlying neuropathic pain relief by the neurosteroid allopregnanolone remain uncertain. We investigated if allopregnanolone attenuates glial extracellular signal-regulated kinase (ERK) activation in the cuneate nucleus (CN) concomitant with neuropathic pain relief in median nerve chronic constriction injury (CCI) model rats. Methods We examined the time course and cellular localization of phosphorylated ERK (p-ERK) in CN after CCI. We subsequently employed microinjection of a mitogen-activated protein kinase kinase (ERK kinase) inhibitor, PD98059, to clarify the role of ERK phosphorylation in neuropathic pain development. Furthermore, we explored the effects of allopregnanolone (by mouth), intra-CN microinjection of γ-aminobutyric acid type A receptor antagonist (bicuculline) or γ-aminobutyric acid type B receptor antagonist (phaclofen) plus allopregnanolone, and allopregnanolone synthesis inhibitor (medroxyprogesterone; subcutaneous) on ERK activation and CCI-induced behavioral hypersensitivity. Results At 7 days post-CCI, p-ERK levels in ipsilateral CN were significantly increased and reached a peak. PD98059 microinjection into the CN 1 day after CCI dose-dependently attenuated injury-induced behavioral hypersensitivity (withdrawal threshold [mean ± SD], 7.4 ± 1.1, 8.7 ± 1.0, and 10.3 ± 0.8 g for 2.0, 2.5, and 3.0 mM PD98059, respectively, at 7 days post-CCI; n = 6 for each dose). Double immunofluorescence showed that p-ERK was localized to both astrocytes and microglia. Allopregnanolone significantly diminished CN p-ERK levels, glial activation, proinflammatory cytokines, and behavioral hypersensitivity after CCI. Bicuculline, but not phaclofen, blocked all effects of allopregnanolone. Medroxyprogesterone treatment reduced endogenous CN allopregnanolone and exacerbated nerve injury-induced neuropathic pain. Conclusions Median nerve injury-induced CN glial ERK activation modulated the development of behavioral hypersensitivity. Allopregnanolone attenuated glial ERK activation and neuropathic pain via γ-aminobutyric acid type A receptors. Reduced endogenous CN allopregnanolone after medroxyprogesterone administration rendered rats more susceptible to CCI-induced neuropathy.

scholarly journals Spinal Macrophage Migration Inhibitory Factor Is a Major Contributor to Rodent Neuropathic Pain-like Hypersensitivity

2011 ◽  
Vol 114 (3) ◽  
pp. 643-659 ◽  
Author(s):  
FuZhou Wang ◽  
ShiQin Xu ◽  
XiaoFeng Shen ◽  
XiRong Guo ◽  
YuZhu Peng ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Migration Inhibitory Factor ◽  
Peripheral Nerve Injury ◽  
Macrophage Migration Inhibitory Factor ◽  
Prostaglandin E ◽  
Macrophage Migration ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

Background Neuropathic pain-like hypersensitivity evoked by peripheral nerve injury is a salient clinical feature of pathologic pain; however, the underlying mechanisms of this condition remain largely unknown. Previous work has confirmed that spinal macrophage migration inhibitory factor (MIF) contributes to the pathogenesis of formalin-induced inflammatory hyperalgesia, but the role for MIF in neuropathic pain is still not well defined. Methods After approval by the Ethical Committee of Animal Use and Care, the sciatic chronic constriction nerve injury-induced rodent model of neuropathic pain was built. The mechanical threshold with von Frey hairs and thermal latency with hot plate were measured, and the expression of spinal MIF, CD74, and downstream extracellular signal-regulated kinase 1/2 signaling cascade was detected. Finally, MIF gene mutation and exogenous recombinant MIF were used for further clarification. Results Intrathecal MIF tautomerase inhibitor reversed sciatic chronic constriction nerve injury-induced pain behaviors. The expression of MIF and CD74 up-regulated in a time-dependent manner in the ipsilateral spinal cord dorsal horn. These changes were associated with the activation of extracellular signal-regulated kinase 1/2 signaling by MIF/CD74 interaction, which subsequently led to up-regulation of interleukin-8 and N-methyl-D-aspartic acid receptor expression and additional production of prostaglandin E(2). Further, MIF gene mutation and exogenous recombinant MIF could desensitize and mimic sciatic chronic constriction nerve injury-evoked pain responses and cellular changes, respectively. Conclusions MIF-associated extracellular signal-regulated kinase 1/2-N-methyl-D-aspartic acid receptor or prostaglandin E(2) cascade accounts for the changes in peripheral nerve injury-induced nociceptive responses.

scholarly journals Pulsed radiofrequency of the median nerve under ultrasound guidance for management of intractable neuropathic pain

2019 ◽  
Vol 47 (8) ◽  
pp. 3978-3984
Author(s):  
Yoo Jung Park ◽  
Man Hee Lee ◽  
So Young Kwon
Keyword(s):  
Neuropathic Pain ◽  
Median Nerve ◽  
Nerve Injury ◽  
Skin Color ◽  
Therapeutic Option ◽  
Pain Clinic ◽  
Intractable Pain ◽  
Pulsed Radiofrequency ◽  
Ultrasound Guided ◽  
Median Nerve Injury

A median nerve injury in the forearm may lead to devastating sequelae if left untreated. Even with appropriate treatments involving microsurgical techniques and postoperative care, patients may still experience lasting neuropathic pain that significantly reduces their quality of life. Pulsed radiofrequency (PRF) is widely performed to alleviate such neuropathic pain caused by trauma. A 47-year-old man visited our pain clinic with allodynia, hyperalgesia, paresthesia, skin color changes, and atrophy in the right forearm. In the orthopedic department, the patient was treated by neurectomy of the median nerve to manage the intractable pain. However, the effect was unsatisfactory. The fourth median nerve block performed in our pain clinic after neurectomy produced good results, and ultrasound-guided PRF of the median nerve was performed. The patient showed 80% relief of symptoms within 5 hours after the procedure. The visual analog scale score for the forearm decreased from 8/10 to 1/10. This case suggests that ultrasound-guided PRF can be a therapeutic option for the management of refractory neuropathic pain after neurectomy in patients with a median nerve injury.

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