Left vagal stimulation induces dynorphin release and suppresses substance P release from the rat thoracic spinal cord during cardiac ischemia

Abstract

Hua, Fang, Jeffrey L. Ardell, and Carole A. Williams. Left vagal stimulation induces dynorphin release and suppresses substance P release from the rat thoracic spinal cord during cardiac ischemia. Am J Physiol Regul Integr Comp Physiol 287: R1468 -R1477, 2004. First published August 5, 2004; doi:10.1152/ajpregu.00251.2004.-Electrostimulatory forms of therapy can reduce angina that arises from activation of cardiac nociceptive afferent fibers during transient ischemia. This study sought to determine the effects of electrical stimulation of left thoracic vagal afferents (C8-T1 level) on the release of putative nociceptive [substance P (SP)] and analgesic [dynorphin (Dyn)] peptides in the dorsal horn at the T4 spinal level during coronary artery occlusion in urethane-anesthetized Sprague-Dawley rats. Release of Dyn and SP was measured by using antibody-coated microprobes. While Dyn and SP had a basal release, occlusion of the left anterior descending coronary artery only affected SP release, causing an increase from lamina I-VII. Left vagal stimulation increased Dyn release, inhibited basal SP release, and blunted the coronary artery occlusion-induced release of SP. Dyn release reflected activation of descending pathways in the thoracic spinal cord, because vagal afferent stimulation still increased the release of Dyn after bilateral dorsal rhizotomy of T2-T5. These results indicate that electrostimulatory therapy, using vagal afferent excitation, may induce analgesia, in part, via inhibition of the release of SP in the spinal cord, possibly through a Dyn-mediated neuronal interaction.antibody-coated microprobes; angina; cardiac nervous system; analgesic peptides; nociceptive peptides INTRACTABLE ANGINA CAN BE one of the more debilitating forms of pain experienced. While myocardial ischemia involves both local changes in myocyte function and reflex alterations in the cardiac nervous system that regulates the myocardium, the perception of angina involves the excessive activation of cardiac sympathetic afferent neurons (16,35). These multimodal sensory afferent neurons respond to ischemia-induced changes in the chemical/mechanical milieu of the heart (16, 35). The cell bodies of these afferents are found in the dorsal root ganglia of spinal segments C 8 -T 9 (cervical 8-thoracic 9), with the majority associated with spinal segments T 2 -T 6 (29) and project mainly to laminae I, V, VII, and X (29). Activated cardiac sympathetic afferent fibers excite cells in the spinal thalamic tract (STT) primarily in T 1 -T 6 spinal segments (4, 41) and C 1 -C 2 segments (8), as well as other ascending tracts, including the spinoreticular, spinomesencephalic, and spinosolitary tracts (16).Clinical treatment for ischemic heart disease focuses on relieving the angina through a hierarchy of treatment modalities, starting with lifestyle changes and progressing through pharmacologically induced coronary vasodilation, angioplasty, and, finally, coronary bypass procedures. Some individuals, however, are refractory to these procedures and ...

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

“…1, probes 4 -6). At the completion of the 10 min in situ time, probes were withdrawn from the spinal cord, washed briefly in ice-cold PBS and incubated with radiolabeled DYN or SP (0.01 Ci/5 l PBS, 7.4) for 24 h at 4°C and then processed as described before (10,12,19,21). Probe placement was verified, as described previously (10,19,21), by visualizing the deposit of 20 nl Pontamine blue dye in a coronal section of T4 that was injected through the final microprobe.…”

“…The release of endogenous immunoreactive-DYN or -SP from sites in the thoracic spinal cord was measured using the antibody-coated microprobe technique, as previously described (10,12,19,21). In all experiments where probes were inserted into the thoracic spinal cord, a set of control probes (designated as in vitro probes) was identically and simultaneously prepared as the in vivo probes.…”

“…In all experiments where probes were inserted into the thoracic spinal cord, a set of control probes (designated as in vitro probes) was identically and simultaneously prepared as the in vivo probes. The in vitro probes were used to determine the sensitivity of the binding of radiolabeled ligand [ 125 I-Tyr 8 SP, or 125 I-Dyn A (1-13) Phoenix Pharmaceuticals] (see 18,19,21) and to confirm the uniformity of binding of the silane and antibody along the probe shaft.…”

“…Since the position of the probe tips was marked by a deposit of blue dye in the spinal cord, sites of release of the peptide could be determined from differences in the optical densities of the probe images on the autoradiographic film. The analysis was carried out based on initial methods described by Hendry et al (18) and modified by this laboratory (10,19,21). A computerized image analysis system (MCID, Imaging Research, Canada) was used to linearly integrate a 4-mm length of the probe images, starting from the probe tip.…”

“…Other forms of electroneuromodulation (i.e., vagal afferent stimulation) have been shown to excite cranial cervical propriospinal neurons (8,13,32), inhibit neurons in the upper thoracic spinal segments (1,14,20), and suppress coronary artery occlusion-induced release of SP from the T4 spinal cord (19), while causing the release of dynorphin (19). These observations led to the hypothesis that electrical neuromodulation at the C2 level, whether initiated by vagal afferent stimulation or direct spinal cord stimulation, attenuates the nociceptive signal (i.e., SP release) at the thoracic level, in part, via the release of an analgesic neuropeptide (such as dynorphin) at the thoracic level.…”