Time-Dependent Changes in Protein Composition of Medial Prefrontal Cortex in Rats with Neuropathic Pain

Chronic pain is associated with time-dependent structural and functional reorganization of the prefrontal cortex that may reflect adaptive pain compensatory and/or maladaptive pain-promoting mechanisms. However, the molecular underpinnings of these changes and whether there are time-dependent relationships to pain progression are not well characterized. In this study, we analyzed protein composition in the medial prefrontal cortex (mPFC) of rats at two timepoints after spinal nerve ligation (SNL) using two-dimensional gel electrophoresis (2D-ELFO) and liquid chromatography with tandem mass spectrometry (LC–MS/MS). SNL, but not sham-operated, rats developed persistent tactile allodynia and thermal hyperalgesia, confirming the presence of experimental neuropathic pain. Two weeks after SNL (early timepoint), we identified 11 proteins involved in signal transduction, protein transport, cell homeostasis, metabolism, and apoptosis, as well as heat-shock proteins and chaperones that were upregulated by more than 1.5-fold compared to the sham-operated rats. Interestingly, there were only four significantly altered proteins identified at 8 weeks after SNL (late timepoint). These findings demonstrate extensive time-dependent modifications of protein expression in the rat mPFC under a chronic neuropathic pain state that might underlie the evolution of chronic pain characterized by early pain-compensatory and later aberrant mechanisms.

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Modulation of SUR1 KATP Channel Subunit Activity in the Peripheral Nervous System Reduces Mechanical Hyperalgesia after Nerve Injury in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20092251 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2251 ◽

Cited By ~ 4

Author(s):

Wing Luu ◽

James Bjork ◽

Erin Salo ◽

Nicole Entenmann ◽

Taylor Jurgenson ◽

...

Keyword(s):

Chronic Pain ◽

Nervous System ◽

Neuropathic Pain ◽

Katp Channel ◽

Thermal Hyperalgesia ◽

Spinal Nerve ◽

Spinal Nerve Ligation ◽

Mechanical Hyperalgesia ◽

K Channel ◽

Nerve Recordings

The ATP-sensitive K+ channel (KATP) is involved in hypersensitivity during chronic pain and is presumed to be a downstream target of mu opioid receptors. Multiple subtypes of KATP channels exist in the peripheral and central nervous system and their activity may be inversely correlated to chronic pain phenotypes in rodents. In this study, we investigated the different KATP channel subunits that could be involved in neuropathic pain in mice. In chronic pain models utilizing spinal nerve ligation, SUR1 and Kir6.2 subunits were found to be significantly downregulated in dorsal root ganglia and the spinal cord. Local or intrathecal administration of SUR1-KATP channel subtype agonists resulted in analgesia after spinal nerve ligation but not SUR2 agonists. In ex-vivo nerve recordings, administration of the SUR1 agonist diazoxide to peripheral nerve terminals decreased mechanically evoked potentials. Genetic knockdown of SUR1 through an associated adenoviral strategy resulted in mechanical hyperalgesia but not thermal hyperalgesia compared to control mice. Behavioral data from neuropathic mice indicate that local reductions in SUR1-subtype KATP channel activity can exacerbate neuropathic pain symptoms. Since neuropathic pain is of major clinical relevance, potassium channels present a target for analgesic therapies, especially since they are expressed in nociceptors and could play an essential role in regulating the excitability of neurons involved in pain-transmission.

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Dopamine Inputs from the Ventral Tegmental Area into the Medial Prefrontal Cortex Modulate Neuropathic Pain-Associated Behaviors in Mice

Cell Reports ◽

10.1016/j.celrep.2020.108393 ◽

2020 ◽

Vol 33 (6) ◽

pp. 108393

Author(s):

Shuo Huang ◽

Zizhen Zhang ◽

Eder Gambeta ◽

Shi Chen Xu ◽

Catherine Thomas ◽

...

Keyword(s):

Neuropathic Pain ◽

Prefrontal Cortex ◽

Ventral Tegmental Area ◽

Medial Prefrontal Cortex ◽

Ventral Tegmental

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Systemic Antiinflammatory Corticosteroid Reduces Mechanical Pain Behavior, Sympathetic Sprouting, and Elevation of Proinflammatory Cytokines in a Rat Model of Neuropathic Pain

Anesthesiology ◽

10.1097/01.anes.0000278907.37774.8d ◽

2007 ◽

Vol 107 (3) ◽

pp. 469-477 ◽

Cited By ~ 64

Author(s):

Huiqing Li ◽

Wenrui Xie ◽

Judith A. Strong ◽

Jun-Ming Zhang

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Nerve Injury ◽

Protein Profile ◽

Spinal Nerve ◽

Interleukin 4 ◽

Sensory Ganglia ◽

Monocyte Chemoattractant Protein 1 ◽

Inflammatory Processes ◽

Sympathetic Sprouting

Background Chronic pain models are commonly defined as either nerve-injury or inflammation models, but recent work suggests inflammatory processes are important in nerve injury-induced pain. Methods In the rat spinal nerve ligation model, the authors examined effects of systemic corticosteroid triamcinolone acetonide (TA) on the cytokine protein profile and sympathetic sprouting in the axotomized sensory ganglia, excitability of sensory neurons, and mechanical sensitivity. Results By postoperative day 3, marked increases (5- to 16-fold) in monocyte chemoattractant protein-1, growth-related oncogene (GRO/KC or CXCL1), and interleukin (IL)-6 were observed, whereas IL-4 and IL-2 levels fell more than fourfold. The increased cytokines and number of sympathetic basket formations in the sensory ganglia were reduced toward normal values by TA given starting at the time of injury. Interleukin-4 and IL-2 levels were not restored by TA. Systemic TA also reduced the firing rate and incidence of bursting activity, but not the overall incidence of spontaneous activity, in large- and medium-sized neurons. Mechanical hypersensitivity on postoperative day 3 was reduced by TA, and some effect could still be observed 4 days after cessation of TA. However, starting TA at day 7 was ineffective. Conclusions Several components of the spinal nerve injury model are responsive to corticosteroid, suggesting inflammatory processes are important in the development of neuropathic pain. The observation that TA was effective when given starting at the time of injury suggests that steroid treatment might alter the development of chronic pain after surgical procedures that involve nerve injury, such as amputation or hernia repair.

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Faculty Opinions recommendation of Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1157091.617189 ◽

2009 ◽

Author(s):

David Borsook

Keyword(s):

Neuropathic Pain ◽

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Functional Reorganization

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Effect of Methylprednisolone on Neuropathic Pain and Spinal Glial Activation in Rats

Anesthesiology ◽

10.1097/00000542-200405000-00029 ◽

2004 ◽

Vol 100 (5) ◽

pp. 1249-1257 ◽

Cited By ~ 55

Author(s):

Kenji Takeda ◽

Shigehito Sawamura ◽

Hiroshi Sekiyama ◽

Hisayoshi Tamai ◽

Kazuo Hanaoka

Keyword(s):

Neuropathic Pain ◽

Mechanical Allodynia ◽

Day Treatment ◽

Thermal Hyperalgesia ◽

Spinal Nerve ◽

Spinal Nerve Ligation ◽

Glial Activation ◽

Pain State ◽

Protein Immunoreactivity ◽

Neuropathic Pain State

Background Basic data are lacking regarding the efficacy and mechanisms of action of corticosteroids in neuropathic pain. Because recent studies indicate that spinal glial activation mediates the pathologic pain states, the authors sought to determine the effects of systemic and intrathecal methylprednisolone on the development and maintenance of neuropathic pain and spinal glial activation in a rat model. Methods Rats were anesthetized, and L5 and L6 spinal nerves were tightly ligated. Then, continuous infusion of systemic (4 mg x kg(-1) x day(-1)) or intrathecal (80 microg x kg(-1) x day(-1)) methylprednisolone or saline was started. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively with von Frey and Hargreaves tests, respectively. Spinal astrocytic activation was evaluated with glial fibrillary acidic protein immunoreactivity on day 7. In other groups of rats, continuous 3-day treatment with intrathecal methylprednisolone or saline was started 7 days after spinal nerve ligation, when neuropathic pain had already developed. Behavioral tests and immunostaining were performed up to 3 weeks after the treatment. Results Spinal nerve ligation induced mechanical allodynia and thermal hyperalgesia on days 4 and 7 postoperatively. Glial fibrillary acidic protein immunoreactivity was remarkably enhanced on day 7. Both systemic and intrathecal methylprednisolone inhibited the development of neuropathic pain states and glial activation. Three-day treatment with intrathecal methylprednisolone reversed existing neuropathic pain state and glial activation up to 3 weeks after the treatment. Conclusion : Systemic and intrathecal methylprednisolone inhibited spinal glial activation and the development and maintenance of a neuropathic pain state in a rat model of spinal nerve ligation.

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