C2 spinal cord stimulation induces dynorphin release from rat T4 spinal cord: potential modulation of myocardial ischemia-sensitive neurons

Abstract

Ding XH, Hua F, Sutherly K, Ardell JL, Williams CA. C2 spinal cord stimulation induces dynorphin release from rat T4 spinal cord: potential modulation of myocardial ischemia-sensitive neurons. Am J Physiol Regul Integr Comp Physiol 295: R1519 -R1528, 2008. First published August 27, 2008 doi:10.1152/ajpregu.00899.2007.-During myocardial ischemia, the cranial cervical spinal cord (C1-C2) modulates the central processing of the cardiac nociceptive signal. This study was done to determine 1) whether C2 SCS-induced release of an analgesic neuropeptide in the dorsal horn of the thoracic (T4) spinal cord; 2) if one of the sources of this analgesic peptide was cervical propriospinal neurons, and 3) if chemical inactivation of C2 neurons altered local T4 substance P (SP) release during concurrent C2 SCS and cardiac ischemia. Ischemia was induced by intermittent occlusion of the left anterior descending coronary artery (CoAO) in urethane-anesthetized Sprague-Dawley rats. Release of dynorphin A (1-13), (DYN) and SP was determined using antibody-coated microprobes inserted into T4. SCS alone induced DYN release from laminae I-V in T4, and this release was maintained during CoAO. C2 injection of the excitotoxin, ibotenic acid, prior to SCS, inhibited T4 DYN release during SCS and ischemia; it also reversed the inhibition of SP release from T4 dorsal laminae during C2 SCS and CoAO. Injection of the -opioid antagonist, nor-binaltorphimine, into T4 also allowed an increased SP release during SCS and CoAO. CoAO increased the number of Fos-positive neurons in T4 dorsal horns but not in the intermediolateral columns (IML), while SCS (either alone or during CoAO) minimized this dorsal horn response to CoAO alone, while inducing T4 IML neuronal recruitment. These results suggest that activation of cervical propriospinal pathways induces DYN release in the thoracic spinal cord, thereby modulating nociceptive signals from the ischemic heart. antibody-coated microprobes; substance P; analgesic peptides; neuromodulation MYOCARDIAL ISCHEMIA ACTIVATES multimodal sensory afferent neurites that respond to changes in the chemical and mechanical milieu of the heart (9, 13, 28). The high cervical spinal cord (at the C1-C2 level) plays an important role in modulating the transmission of the ischemic cardiac afferent sensory signal within the thoracic spinal cord via descending inhibitory propriospinal pathways (9,13,14). High cervical spinal cord stimulation (SCS) has been shown to be effective in treating refractory angina with no detrimental effects on cardiac function (14,23,26). Our laboratory has investigated the neurochemical mediation of the cardiac ischemic signal and the effects of electroneuromodulation on the release of some of the neuropeptides that may be involved with the transmission of this signal (10, 19 -21). Recent evidence indicates that substance P (SP) is released from dorsal horn laminae in the thoracic spinal cord in response to cardiac ischemia (10, 21), induced by brief coronary artery occlusion and that this peptid...

Dorsal spinal cord stimulation obtunds the capacity of intrathoracic extracardiac neurons to transduce myocardial ischemia

“…In animal models of reduced coronary reserve, SCS mitigates the ST segment deviations associated with chemical activation of intrathoracic adrenergic neurons (14). SCS by itself (18), or in combination with coronary artery occlusion (17), increases cFos expression within subpopula- . C: dots in the raster sweep plot represent action potentials generated by 4 neurons recorded during the 1,792 cardiac cycles.…”

“…Electrical neuromodulation impacts on the dynamic interactions among autonomic afferent and efferent neurons mediated via, as yet poorly defined, spinal cord and peripheral neural circuits (18,20,35,43). Centrally, SCS reduces the release of neuropeptides from cardiac nociceptive afferent neurons (17), reduces intrasegmental and supraspinal transmission of cardiac nociceptive information (20,35), and increases the activity of a subpopulation of thoracic sympathetic preganglionic efferent neurons (17,18).…”

“…Centrally, SCS reduces the release of neuropeptides from cardiac nociceptive afferent neurons (17), reduces intrasegmental and supraspinal transmission of cardiac nociceptive information (20,35), and increases the activity of a subpopulation of thoracic sympathetic preganglionic efferent neurons (17,18). Peripherally, SCS reduces the activity generated by intrinsic cardiac neurons by ϳ70% at baseline as well as when they are activated by transient ventricular ischemia (13,21).…”

Continuous Spinal Cord Stimulation Reduced Cardiac Ischaemia/Reperfusion Injury in a Rat Model

“…Research for the underlying mechanisms has largely concentrated on the balance between myocardial oxygen consumption and oxygen supply after SCS, but recent experimental and clinical studies failed to detect an increase in local flow or a redistribution of myocardial blood flow following SCS [11,12]. Although the specific neurotransmitters that modulated by SCS remain poorly elucidated, available data showed that SCS could induce endogenous opioids release from cardiac sympathetic afferent nerve terminals [13,14]. Moreover, recent studies have shown that continuous opioid receptor activation…”

Autonomic Regulation Therapy in Heart Failure

“…At the spinal cord itself, SCS induces the release of neuromodulators such as dynorphin, blunts the release of primary afferent related neurotransmitters such as substance P, and alters activity with sympathetic preganglionic neurons contained within the intermediolateral cell column 68, 69 . As such it thereby alters ascending signals to higher centers 15, 57, 58 and alters autonomic efferent outflows to peripheral aspects of the cardiac nervous system.…”