“…Cannabinoid resistance is implicated in opioid inefficacy [ 69 ], since neuroinflammation persists if cannabinoid modulation fails to suppress astrocyte and microglia activity. Considering this intimate relationship between cannabinoid and opioid systems in DHSC and the fact that MCS activates descending analgesic pathways [ 21 , 25 , 26 , 70 ] and inhibits spinal nociceptive neurons [ 31 , 71 ], we propose that the following spinal circuitry is involved in MCS-induced analgesia: activation of spinal cannabinoid neurons causes them to release endocannabinoids, which inhibit astrocyte and microglia activity, thus decreasing neuroexcitatory cytokine secretion and suppressing nociceptive neuron excitability through opioid activation (Figure 5 ). Figure 5 Motor cortex stimulation (MCS) effectiveness and refractoriness: cannabinoids, opioids, and neuroinflammation.…”
BackgroundMotor cortex stimulation (MCS) is an effective treatment in neuropathic pain refractory to pharmacological management. However, analgesia is not satisfactorily obtained in one third of patients. Given the importance of understanding the mechanisms to overcome therapeutic limitations, we addressed the question: what mechanisms can explain both MCS effectiveness and refractoriness? Considering the crucial role of spinal neuroimmune activation in neuropathic pain pathophysiology, we hypothesized that modulation of spinal astrocyte and microglia activity is one of the mechanisms of action of MCS.MethodsRats with peripheral neuropathy (chronic nerve injury model) underwent MCS and were evaluated with a nociceptive test. Following the test, these animals were divided into two groups: MCS-responsive and MCS-refractory. We also evaluated a group of neuropathic rats not stimulated and a group of sham-operated rats. Some assays included rats with peripheral neuropathy that were treated with AM251 (a cannabinoid antagonist/inverse agonist) or saline before MCS. Finally, we performed immunohistochemical analyses of glial cells (microglia and astrocytes), cytokines (TNF-α and IL-1β), cannabinoid type 2 (CB2), μ-opioid (MOR), and purinergic P2X4 receptors in the dorsal horn of the spinal cord (DHSC).FindingsMCS reversed mechanical hyperalgesia, inhibited astrocyte and microglial activity, decreased proinflammatory cytokine staining, enhanced CB2 staining, and downregulated P2X4 receptors in the DHSC ipsilateral to sciatic injury. Spinal MOR staining was also inhibited upon MCS. Pre-treatment with AM251 blocked the effects of MCS, including the inhibitory mechanism on cells. Finally, MCS-refractory animals showed similar CB2, but higher P2X4 and MOR staining intensity in the DHSC in comparison to MCS-responsive rats.ConclusionsThese results indicate that MCS induces analgesia through a spinal anti-neuroinflammatory effect and the activation of the cannabinoid and opioid systems via descending inhibitory pathways. As a possible explanation for MCS refractoriness, we propose that CB2 activation is compromised, leading to cannabinoid resistance and consequently to the perpetuation of neuroinflammation and opioid inefficacy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0216-1) contains supplementary material, which is available to authorized users.
“…Cannabinoid resistance is implicated in opioid inefficacy [ 69 ], since neuroinflammation persists if cannabinoid modulation fails to suppress astrocyte and microglia activity. Considering this intimate relationship between cannabinoid and opioid systems in DHSC and the fact that MCS activates descending analgesic pathways [ 21 , 25 , 26 , 70 ] and inhibits spinal nociceptive neurons [ 31 , 71 ], we propose that the following spinal circuitry is involved in MCS-induced analgesia: activation of spinal cannabinoid neurons causes them to release endocannabinoids, which inhibit astrocyte and microglia activity, thus decreasing neuroexcitatory cytokine secretion and suppressing nociceptive neuron excitability through opioid activation (Figure 5 ). Figure 5 Motor cortex stimulation (MCS) effectiveness and refractoriness: cannabinoids, opioids, and neuroinflammation.…”
BackgroundMotor cortex stimulation (MCS) is an effective treatment in neuropathic pain refractory to pharmacological management. However, analgesia is not satisfactorily obtained in one third of patients. Given the importance of understanding the mechanisms to overcome therapeutic limitations, we addressed the question: what mechanisms can explain both MCS effectiveness and refractoriness? Considering the crucial role of spinal neuroimmune activation in neuropathic pain pathophysiology, we hypothesized that modulation of spinal astrocyte and microglia activity is one of the mechanisms of action of MCS.MethodsRats with peripheral neuropathy (chronic nerve injury model) underwent MCS and were evaluated with a nociceptive test. Following the test, these animals were divided into two groups: MCS-responsive and MCS-refractory. We also evaluated a group of neuropathic rats not stimulated and a group of sham-operated rats. Some assays included rats with peripheral neuropathy that were treated with AM251 (a cannabinoid antagonist/inverse agonist) or saline before MCS. Finally, we performed immunohistochemical analyses of glial cells (microglia and astrocytes), cytokines (TNF-α and IL-1β), cannabinoid type 2 (CB2), μ-opioid (MOR), and purinergic P2X4 receptors in the dorsal horn of the spinal cord (DHSC).FindingsMCS reversed mechanical hyperalgesia, inhibited astrocyte and microglial activity, decreased proinflammatory cytokine staining, enhanced CB2 staining, and downregulated P2X4 receptors in the DHSC ipsilateral to sciatic injury. Spinal MOR staining was also inhibited upon MCS. Pre-treatment with AM251 blocked the effects of MCS, including the inhibitory mechanism on cells. Finally, MCS-refractory animals showed similar CB2, but higher P2X4 and MOR staining intensity in the DHSC in comparison to MCS-responsive rats.ConclusionsThese results indicate that MCS induces analgesia through a spinal anti-neuroinflammatory effect and the activation of the cannabinoid and opioid systems via descending inhibitory pathways. As a possible explanation for MCS refractoriness, we propose that CB2 activation is compromised, leading to cannabinoid resistance and consequently to the perpetuation of neuroinflammation and opioid inefficacy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0216-1) contains supplementary material, which is available to authorized users.
“…The absence of significant somatotopic effects could be due in part to technical reasons, related to the lack of precise target localization in early studies conducted without MRI neuronavigation (Lefaucheur et al, 2004(Lefaucheur et al, , 2006. However, somatotopic-independent analgesia may also be related to neurotransmitter release by repetitive cortical stimulation, since enhanced secretion of opioids and/or dopamine has been reported following stimulation of both intracranial MCS (Viisanen et al, 2012;Chiou et al, 2013) and noninvasive rTMS of motor and dorsolateral prefrontal cortices (Taylor et al, 2012;Jaaskelainen et al, 2014;Lamusuo et al, 2017). Facing such uncertainties, in this study we assessed systematically the possible existence of a somatotopic rTMS effect in a representative sample of neuropathic pain patients.…”
Strict somatotopic targeting of rTMS does not appear warranted for the treatment of upper limb or face NP. Since the hand motor area is easier to target and provides better results, it might be privileged for both types of pain.
“…[15] и R. Chiou и соавт. [16] выдвигают гипотезы о снижении ингибиции нейронов периакведуктального серого вещества и подавлении ноцицептивных импульсов со спинного мозга.…”
Цель исследования-демонстрация собственных результатов лечения трудно купируемой деафферентационной лицевой боли методом стимуляции моторной коры и обзор литературы по данной проблеме. Материал и методы. В исследование включены 8 пациентов (3 мужчины и 5 женщин) с деафферентационной лицевой болью, которым на базе Иллинойского университета (Чикаго) в 2004-2016 гг. и ФГБУ ФЦН (Новосибирск) в 2017 г. была установлена система постоянной стимуляции моторной коры головного мозга. Возраст больных варьировал от 37 лет до 81 года (средний возраст 57,5 года). Оценка выраженности болевого синдрома проводилась при поступлении в стационар, при выписке и в катамнезе с использованием визуальной аналоговой шкалы боли, шкалы боли Неврологического института Barrow (BNIPS) и шкалы McLaughlin. Результаты. Сразу после вмешательства значительное улучшение в виде купирования боли на 80-100% отмечено у 4 больных. Интенсивность болевого синдрома при выписке из стационара в среднем снизилась на 55%. В катамнезе 3 из 8 пациентов оценили эффективность стимуляции моторной коры по шкале McLaughlin как «очень хороший» результат, 4-как «хороший» и 1-как «неудовлетворительный». Заключение. Представленные нами результаты и последние исследования других авторов показывают, что стимуляция моторной коры является одной из опций лечения деафферентационной лицевой боли. Даже некоторое уменьшение мучительной и изнуряющей боли, которое пациенты оценивают как «хороший эффект», дает основания для применения метода. Для определения более четких критериев отбора пациентов на этот вид лечения и повышения эффективности стимуляции необходимы дальнейшие исследования.
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