Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson’s Disease

In the present study, we investigated whether restoring descending noradrenergic inhibitory tone can attenuate pain in a PD rat model, which was established by stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into the bilateral striatum (CPu). PD rats developed thermal and mechanical hypersensitivity at the 4th week after surgery. HPLC analysis showed that NE content, but not dopamine or 5-HT, significantly decreased in lumbar spinal cord in PD rats. Additional noradrenergic depletion by injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) aggravated pain hypersensitivity in PD rats. At the 5th week after injection of 6-OHDA, systemic treatment with pharmacological norepinephrine (NE) precursor droxidopa (L-DOPS) orα2 adrenoceptor agonist clonidine significantly attenuated thermal and mechanical pain hypersensitivity in PD rats. Furthermore, application of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) reuptake inhibitors duloxetine, but not 5-HT selective reuptake inhibitors sertraline, significantly inhibited thermal and mechanical pain hypersensitivity in PD rats. Systemic administration of Madopar (L-DOPA) or the D2/D3 agonist pramipexole slightly inhibited the thermal, but not mechanical, hypersensitivity in PD rats. Thus, our study revealed that impairment of descending noradrenergic system may play a key role in PD-associated pain and restoring spinal noradrenergic inhibitory tone may serve as a novel strategy to manage PD-associated pain.

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Multi-pronged neuromodulation intervention engages the residual motor circuitry to facilitate walking in a rat model of spinal cord injury

Nature Communications ◽

10.1038/s41467-021-22137-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Marco Bonizzato ◽

Nicholas D. James ◽

Galyna Pidpruzhnykova ◽

Natalia Pavlova ◽

Polina Shkorbatova ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Model ◽

Stress Responses ◽

Learning Algorithm ◽

Lumbar Spinal Cord ◽

Cord Injury ◽

Potential Synergy ◽

Lumbar Spinal ◽

Deep Brain

AbstractA spinal cord injury usually spares some components of the locomotor circuitry. Deep brain stimulation (DBS) of the midbrain locomotor region and epidural electrical stimulation of the lumbar spinal cord (EES) are being used to tap into this spared circuitry to enable locomotion in humans with spinal cord injury. While appealing, the potential synergy between DBS and EES remains unknown. Here, we report the synergistic facilitation of locomotion when DBS is combined with EES in a rat model of severe contusion spinal cord injury leading to leg paralysis. However, this synergy requires high amplitudes of DBS, which triggers forced locomotion associated with stress responses. To suppress these undesired responses, we link DBS to the intention to walk, decoded from cortical activity using a robust, rapidly calibrated unsupervised learning algorithm. This contingency amplifies the supraspinal descending command while empowering the rats into volitional walking. However, the resulting improvements may not outweigh the complex technological framework necessary to establish viable therapeutic conditions.

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Chimerization of astroglial population in the lumbar spinal cord after mesenchymal stem cell transplantation prolongs survival in a rat model of amyotrophic lateral sclerosis

Journal of Neuroscience Research ◽

10.1002/jnr.22038 ◽

2009 ◽

Vol 87 (9) ◽

pp. 2034-2046 ◽

Cited By ~ 68

Author(s):

Cédric Boucherie ◽

Sabrina Schäfer ◽

Patricia Lavand'homme ◽

Jean-Marie Maloteaux ◽

Emmanuel Hermans

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Stem Cell Transplantation ◽

Rat Model ◽

Lumbar Spinal Cord ◽

Mesenchymal Stem Cell Transplantation ◽

Lumbar Spinal ◽

Lateral Sclerosis

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Coenzyme Q10 influences on the levels of TNF-α and IL-10 and the ratio of Bax/Bcl2 in a menopausal rat model following lumbar spinal cord injury

IBRO Reports ◽

10.1016/j.ibror.2019.07.1342 ◽

2019 ◽

Vol 6 ◽

pp. S422

Author(s):

Maryam Soleimani ◽

Seyed Behnamedin Jameie ◽

Sajad Hassanzadeh

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Model ◽

Coenzyme Q10 ◽

Lumbar Spinal Cord ◽

Model Following ◽

Tnf Α ◽

Cord Injury ◽

Lumbar Spinal

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The Mechanical Antihyperalgesic Effect of Intrathecally Administered MPV-2426, a Novel α2-Adrenoceptor Agonist, in a Rat Model of Postoperative Pain

Anesthesiology ◽

10.1097/00000542-200006000-00034 ◽

2000 ◽

Vol 92 (6) ◽

pp. 1740-1745 ◽

Cited By ~ 24

Author(s):

Tiina Onttonen ◽

Antti Pertovaara

Keyword(s):

Postoperative Pain ◽

Rat Model ◽

Spinal Pain ◽

Mechanical Hyperalgesia ◽

Lumbar Spinal Cord ◽

Preoperative Treatment ◽

Withdrawal Threshold ◽

Plantar Aspect ◽

Adrenoceptor Agonist ◽

Alpha2 Adrenoceptor

Background MPV-2426 is a novel alpha2-adrenoceptor agonist developed for spinal pain therapy. It has proved to be effective in physiologic and neuropathic conditions. In the current study its effectiveness on mechanical hyperalgesia was assessed in a rat model of postoperative pain. Methods Rats with intrathecal catheters were anesthetized with pentobarbital, and a 1-cm incision was made in the plantar aspect of the foot and closed. During postoperative days 1 and 2 the antihyperalgesic effects induced by intrathecal MPV-2426, clonidine, and dexmedetomidine were determined by assessing the hind limb withdrawal threshold to calibrated von Frey hairs applied to the skin of the hind paw adjacent to the wound. Results MPV-2426 administered into the lumbar spinal cord produced a dose-dependent (0.3-10 microg) attenuation of the mechanical hyperalgesia, and this antihyperalgesic effect was completely reversed by yohimbine (1 mg/kg, subcutaneous), an alpha2-adrenoceptor antagonist. Dexmedetomidine (1-3 microg) produced an equipotent antihyperalgesic effect, whereas the effect of clonidine (1-10 microg) was markedly weaker. MPV-2426 (10 microg in 20 microl) administered adjacent to the wound did not produce any effect. Preoperative treatment with an antihyperalgesic dose of MPV-2426 did not prevent the development of hyperalgesia. Conclusions Intrathecal MPV-2426 dose-dependently attenuates postoperative hyperalgesia to mechanical stimulation because of an action on alpha2 adrenoceptors. Its antihyperalgesic action is as effective as that produced by dexmedetomidine and is considerably stronger than that produced by clonidine. However, preoperative treatment with MPV-2426 does not prevent the development of postoperative hyperalgesia.

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