Spinal cord stimulation reduces cardiac pain through microglial deactivation in rats with chronic myocardial ischemia

Abstract

Angina pectoris is cardiac pain that is a common clinical symptom often resulting from myocardial ischemia. Spinal cord stimulation (SCS) is effective in treating refractory angina pectoris, but its underlying mechanisms have not been fully elucidated. The spinal dorsal horn is the first region of the central nervous system that receives nociceptive information; it is also the target of SCS. In the spinal cord, glial (astrocytes and microglia) activation is involved in the initiation and persistence of chronic pain. Thus, the present study investigated the possible cardiac pain-relieving effects of SCS on spinal dorsal horn glia in chronic myocardial ischemia (CMI). CMI was established by left anterior descending artery ligation surgery, which induced significant spontaneous/ongoing cardiac pain behaviors, as measured using the open field test in rats. SCS effectively improved such behaviors as shown by open field and conditioned place preference tests in CMI model rats. SCS suppressed CMI-induced spinal dorsal horn microglial activation, with downregulation of ionized calcium-binding adaptor protein-1 expression. Moreover, SCS inhibited CMI-induced spinal expression of phosphorylated-p38 MAPK, which was specifically colocalized with the spinal dorsal horn microglia rather than astrocytes and neurons. Furthermore, SCS could depress spinal neuroinflammation by suppressing CMI-induced IL-1β and TNF-α release. Intrathecal administration of minocycline, a microglial inhibitor, alleviated the cardiac pain behaviors in CMI model rats. In addition, the injection of fractalkine (microglia-activating factor) partially reversed the SCS-produced analgesic effects on CMI-induced cardiac pain. These results indicated that the therapeutic mechanism of SCS on CMI may occur partially through the inhibition of spinal microglial p38 MAPK pathway activation. The present study identified a novel mechanism underlying the SCS-produced analgesic effects on chronic cardiac pain.

Spinal Cord Stimulation Alleviates Neuropathic Pain by Attenuating Microglial Activation via Reducing Colony-Stimulating Factor 1 Levels in the Spinal Cord in a Rat Model of Chronic Constriction Injury

“… 15 , 16 Another study showed that SCS reduces chronic cardiac pain partially by inhibiting spinal microglial activation and, thus, potentially downregulates the expression of proinflammatory mediators, such as IL-1β and TNF-α. 30 Moreover, other studies showed that SCS might reduce microglial activation at the level of the spinal cord. 13 , 16 , 20 It is notable that our findings are contrary to results from a recent study showing that conventional SCS exacerbated microglial activation in the lumbar cord of CCI rats during the maintenance phase of NP.…”

“…Activation and CSF1 Levels in CCI Model Spinal Cord Despite that SCS could not normalize the PWT, it caused a significant increase in PWT, indicating that SCS is able to produce analgesic effects in CCI rats. Previous studies reported that a small but significant reduction in mechanical hypersensitivity could persist for up to 5 days in CCI rats even after the cessation of SCS, 26,[28][29][30] thus, this cannot be completely explained by GCT alone. Our study demonstrated that repeated SCS attenuated microglial activation, as indicated by reduced immunoreactivity of CD11b in the ipsilateral DH in CCI rats, is in agreement with results of previous studies showing that continuous SCS treatment for 4 days relieved NP by inhibiting activation of microglia and astrocytes in the spinal cord of rats with spared nerve injury.…”

Improvement of brain perfusion in patients with chronic brain ischemia at epidural spinal cord electrical stimulation

“…For this purpose, methods of magnetic and electrical stimulation of the central nervous system are widely used. Electrical stimulation of the central and peripheral parts of the nervous system (stimulation of the structures of the autonomic nervous system, epidural electrical stimulation of the spinal cord, electrical stimulation of individual nerves and nerve bundles) has now found wide application and has shown high efficiency in clinical practice for the functional correction of many neurological and neurosurgical diseases, such as Parkinson's disease, essential tremor, epilepsy, spastic and pain syndromes (6,11,13,31). Considering the high frequency of concomitant "age-related" diseases accompanied by chronic pain syndromes, we conducted a study to identify possible positive effects of electrical spinal cord stimulation in elderly patients with chronic cerebral ischemia.…”

“…The high social significance and prevalence of these disorders determines the relevance of finding new ways to correct these conditions, however, existing pharmacological methods that improve the functional state of the central nervous system (CNS) do not always meet the expectations of both doctors and patients (3,4). In recent years, various methods of neuromodulation based on epidural electrical stimulation of the spinal cord have been proposed in clinical practice for the correction of peripheral hemodynamic disorders in patients suffering from refractory angina pectoris or peripheral vasculopathy (6)(7)(8)(9)(10)(11). Also, in many experimental and clinical studies, a positive effect of electrical stimulation of the spinal cord on the hemodynamic and functional parameters of the brain was noted in certain pathological conditions associated with dysfunction of the vascular bed, such as ischemia, subarachnoid hemorrhage, head trauma and brain tumors (10,(12)(13)(14)(15)(16).…”

Spinal cord stimulation for refractory pericarditis: a case report and a review of the mechanism of action

“…This study suggests that SCS exhibits anti-inflammatory effects ( 24 ). Moreover, Wang et al ( 25 ) reported the ability of SCS to decrease spinal neuroinflammation induced by cardiac myocardial infarction in rats. This effect is achieved by inhibiting spinal microglial p38 in the mitogen-activated protein kinase pathway (MAPK), which subsequently reduces the levels of proinflammatory mediators IL-1β and TNF-α in the spinal cord.…”