Neurochemical effects of motor cortex stimulation in the periaqueductal gray during neuropathic pain

OBJECTIVEMotor cortex stimulation (MCS) is a neurosurgical technique used to treat patients with refractory neuropathic pain syndromes. MCS activates the periaqueductal gray (PAG) matter, which is one of the major centers of the descending pain inhibitory system. However, the neurochemical mechanisms in the PAG that underlie the analgesic effect of MCS have not yet been described. The main goal of this study was to investigate the neurochemical mechanisms involved in the analgesic effect induced by MCS in neuropathic pain. Specifically, we investigated the release of γ-aminobutyric acid (GABA), glycine, and glutamate in the PAG and performed pharmacological antagonism experiments to validate of our findings.METHODSMale Wistar rats with surgically induced chronic constriction of the sciatic nerve, along with sham-operated rats and naive rats, were implanted with both unilateral transdural electrodes in the motor cortex and a microdialysis guide cannula in the PAG and subjected to MCS. The MCS was delivered in single 15-minute sessions. Neurotransmitter release was evaluated in the PAG before, during, and after MCS. Quantification of the neurotransmitters GABA, glycine, and glutamate was performed using a high-performance liquid chromatography system. The mechanical nociceptive threshold was evaluated initially, on the 14th day following the surgery, and during the MCS. In another group of neuropathic rats, once the analgesic effect after MCS was confirmed by the mechanical nociceptive test, rats were microinjected with saline or a glycine antagonist (strychnine), a GABA antagonist (bicuculline), or a combination of glycine and GABA antagonists (strychnine+bicuculline) and reevaluated for the mechanical nociceptive threshold during MCS.RESULTSMCS reversed the hyperalgesia induced by peripheral neuropathy in the rats with chronic sciatic nerve constriction and induced a significant increase in the glycine and GABA levels in the PAG in comparison with the naive and sham-treated rats. The glutamate levels remained stable under all conditions. The antagonism of glycine, GABA, and the combination of glycine and GABA reversed the MCS-induced analgesia.CONCLUSIONSThese results suggest that the neurotransmitters glycine and GABA released in the PAG may be involved in the analgesia induced by cortical stimulation in animals with neuropathic pain. Further investigation of the mechanisms involved in MCS-induced analgesia may contribute to clinical improvements for the treatment of persistent neuropathic pain syndromes.

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Motor Cortex Stimulation for the Treatment of Neuropathic Pain Syndromes

Neurosurgical Pain Management ◽

10.1016/b978-0-7216-9241-8.50021-x ◽

2004 ◽

pp. 160-164

Author(s):

J BROWN

Keyword(s):

Neuropathic Pain ◽

Motor Cortex ◽

Motor Cortex Stimulation ◽

Pain Syndromes

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Clinical Significance of Invasive Motor Cortex Stimulation for Trigeminal Facial Neuropathic Pain Syndromes

Neurosurgery ◽

10.1227/neu.0000000000001353 ◽

2016 ◽

Vol 79 (5) ◽

pp. 655-666 ◽

Cited By ~ 12

Author(s):

Dirk Rasche ◽

Volker M. Tronnier

Keyword(s):

Neuropathic Pain ◽

Motor Cortex ◽

Test Trial ◽

Visual Analog Scale ◽

False Positive ◽

Motor Cortex Stimulation ◽

Analog Scale ◽

Pain Syndromes ◽

Double Blinded

Abstract BACKGROUND: Invasive neuromodulation of the cortical surface for various chronic pain syndromes has been performed for >20 years. The significance of motor cortex stimulation (MCS) in chronic trigeminal neuropathic pain (TNP) syndromes remains unclear. Different techniques are performed worldwide in regard to operative procedure, stimulation parameters, test trials, and implanted materials. OBJECTIVE: To present the clinical experiences of a single center with MCS, surgical approach, complications, and follow-up as a prospective, noncontrolled clinical trial. METHODS: The implantation of epidural leads over the motor cortex was performed via a burr hole technique with neuronavigation and intraoperative neurostimulation. Special focus was placed on a standardized test trial with an external stimulation device and the implementation of a double-blinded or placebo test phase to identify false-positive responders. RESULTS: A total of 36 patients with TNP were operated on, and MCS was performed. In 26 of the 36 patients (72%), a significant pain reduction from a mean of 8.11 to 4.58 (on the visual analog scale) during the test trial was achieved (P <.05). Six patients were identified as false-positive responders (17%). At the last available follow-up of 26 patients (mean, 5.6 years), active MCS led to a significant pain reduction compared with the preoperative pain ratings (mean visual analog scale score, 5.01; P <.05). CONCLUSION: MCS is an additional therapeutic option for patients with refractory chronic TNP, and significant long-term pain suppression can be achieved. Placebo or double-blinded testing is mandatory.

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Motor cortex stimulation in neuropathic pain. Correlations between analgesic effect and hemodynamic changes in the brain. A PET study

NeuroImage ◽

10.1016/j.neuroimage.2006.08.037 ◽

2007 ◽

Vol 34 (1) ◽

pp. 310-321 ◽

Cited By ~ 174

Author(s):

Roland Peyron ◽

Isabelle Faillenot ◽

Patrick Mertens ◽

Bernard Laurent ◽

Luis Garcia-Larrea

Keyword(s):

Neuropathic Pain ◽

Motor Cortex ◽

Analgesic Effect ◽

Motor Cortex Stimulation ◽

Hemodynamic Changes ◽

The Brain

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311 MOTOR CORTEX STIMULATION FOR THE TREATMENT OF DIFFERENT NEUROPATHIC PAIN SYNDROMES

European Journal of Pain ◽

10.1016/j.ejpain.2007.03.326 ◽

2007 ◽

Vol 11 (S1) ◽

pp. S138-S138

Author(s):

V.M. Tronnier ◽

D. Klase ◽

D. Rasche

Keyword(s):

Neuropathic Pain ◽

Motor Cortex ◽

Motor Cortex Stimulation ◽

Pain Syndromes

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Motor cortex stimulation for neuropathic pain syndromes

Neuroreport ◽

10.1097/wnr.0000000000000174 ◽

2014 ◽

Vol 25 (9) ◽

pp. 715-717 ◽

Cited By ~ 12

Author(s):

Robert J. Buchanan ◽

David Darrow ◽

Daniel Monsivais ◽

Zoltan Nadasdy ◽

Klevest Gjini

Keyword(s):

Neuropathic Pain ◽

Motor Cortex ◽

Motor Cortex Stimulation ◽

Pain Syndromes

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Motor Cortex Stimulation for Neuropathic Pain: A Randomized Cross-over Trial

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2015.292 ◽

2015 ◽

Vol 42 (6) ◽

pp. 401-409 ◽

Cited By ~ 14

Author(s):

Julia A.E. Radic ◽

Ian Beauprie ◽

Paula Chiasson ◽

Zelma H.T. Kiss ◽

Robert M. Brownstone

Keyword(s):

Neuropathic Pain ◽

Motor Cortex ◽

Upper Extremity ◽

Outcome Measures ◽

Secondary Outcome ◽

Mcgill Pain Questionnaire ◽

Motor Cortex Stimulation ◽

Pain Syndromes ◽

Sf 36 ◽

Quality Of Life Scale

AbstractBackground: Chronic motor cortex stimulation (MCS) has been used to treat medically refractory neuropathic pain over the past 20 years. We investigated this procedure using a prospective multicentre randomized blinded crossover trial. Methods: Twelve subjects with three different neuropathic pain syndromes had placement of MCS systems after which they were randomized to receive low (“subtherapeutic”) or high (“therapeutic”) stimulation for 12 weeks, followed by a crossover to the other treatment group for 12 weeks. The primary outcome measure was the pain visual analogue scale (VAS). Secondary outcome measures included McGill Pain Questionnaire (MPQ), Beck Depression Inventory-II, medication log, work status, global impression of change, and SF-36 quality of life scale. Results: The trial was halted early due to lack of efficacy. One subject withdrew early due to protocol violation and five subjects withdrew early due to transient adverse events. Six subjects with upper extremity pain completed the study. There was no significant change in VAS with low or high stimulation and no significant improvement in any of the outcome measures from low to high stimulation. SF-36 role physical and mental health scores were worse with high compared to low stimulation (p=0.024, p=0.005). Conclusions: We failed to show that MCS is an effective treatment for refractory upper extremity neuropathic pain and suggest that previous studies may have been skewed by placebo effects, or ours by nocebo. We suggest that a healthy degree of skepticism is warranted when considering this invasive therapy for upper extremity pain syndromes.

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Faculty Opinions recommendation of Treatment of central deafferentation and trigeminal neuropathic pain by motor cortex stimulation: report of a series of 20 patients.

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

10.3410/f.725993347.793558721 ◽

2019 ◽

Author(s):

Mark Obermann

Keyword(s):

Neuropathic Pain ◽

Motor Cortex ◽

Motor Cortex Stimulation ◽

Trigeminal Neuropathic Pain

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Pre-motor versus motor cerebral cortex neuromodulation for chronic neuropathic pain

Scientific Reports ◽

10.1038/s41598-021-91872-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Igor Lavrov ◽

Timur Latypov ◽

Elvira Mukhametova ◽

Brian Lundstrom ◽

Paola Sandroni ◽

...

Keyword(s):

Neuropathic Pain ◽

Cerebral Cortex ◽

Motor Cortex ◽

Initial Assessment ◽

Motor Cortex Stimulation ◽

Chronic Neuropathic Pain ◽

Long Term Effect ◽

Stimulation Of

AbstractElectrical stimulation of the cerebral cortex (ESCC) has been used to treat intractable neuropathic pain for nearly two decades, however, no standardized approach for this technique has been developed. In order to optimize targeting and validate the effect of ESCC before placing the permanent grid, we introduced initial assessment with trial stimulation, using a temporary grid of subdural electrodes. In this retrospective study we evaluate the role of electrode location on cerebral cortex in control of neuropathic pain and the role of trial stimulation in target-optimization for ESCC. Location of the temporary grid electrodes and location of permanent electrodes were evaluated in correlation with the long-term efficacy of ESCC. The results of this study demonstrate that the long-term effect of subdural pre-motor cortex stimulation is at least the same or higher compare to effect of subdural motor or combined pre-motor and motor cortex stimulation. These results also demonstrate that the initial trial stimulation helps to optimize permanent electrode positions in relation to the optimal functional target that is critical in cases when brain shift is expected. Proposed methodology and novel results open a new direction for development of neuromodulation techniques to control chronic neuropathic pain.

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Tramadol effects on clinical variables and the mechanical nociceptive threshold in horses

Ciência Rural ◽

10.1590/s0103-84782014000300021 ◽

2014 ◽

Vol 44 (3) ◽

pp. 517-523 ◽

Cited By ~ 4

Author(s):

Leandro Guimarães Franco ◽

Juan Carlos Duque Moreno ◽

Antônio Raphael Teixeira Neto ◽

Moisés Caetano e Souza ◽

Luiz Antônio Franco da Silva

Keyword(s):

Heart Rate ◽

Arterial Pressure ◽

Respiratory Rate ◽

Analgesic Effect ◽

Randomized Study ◽

Behavioral Changes ◽

Behavior Changes ◽

Clinical Effects ◽

Nociceptive Threshold ◽

Mechanical Nociceptive Threshold

This study assessed the clinical effects and the mechanical antinociceptive potential of intravenous (IV) tramadol in horses.A blinded and randomized study was designed with 7 horses treated with 1 (Tr1), 2 (Tr2) or 3 (Tr3) mg kg-1 of tramadol IV. The heart rate, respiratory rate (fR), arterial pressure, degree of sedation, gastrointestinal motility (GI), behavior changes and the mechanical nociceptive threshold (MNT) were evaluated. The MNT was determined with von Frey device method.Tr3 had a significant increase in their fR and more pronounced behavioral changes than other treatments.The Tr1 showed a significant increase in arterial pressure. The GI reduced significantly, mainly in Tr2. The tramadol did not change the MNT of the horses.The clinical alterations observed with the different treatments were considered mild and transitory, being most evident in Tr2. However the tramadol did not have any analgesic effect with any of the doses evaluated.

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