Functional role of peripheral opioid receptors in the regulation of cardiac spinal afferent nerve activity during myocardial ischemia

Abstract

Thinly myelinated Aδ-fiber and unmyelinated C-fiber cardiac sympathetic (spinal) sensory nerve fibers are activated during myocardial ischemia to transmit the sensation of angina pectoris. Although recent observations showed that myocardial ischemia increases the concentrations of opioid peptides and that the stimulation of peripheral opioid receptors inhibits chemically induced visceral and somatic nociception, the role of opioids in cardiac spinal afferent signaling during myocardial ischemia has not been studied. The present study tested the hypothesis that peripheral opioid receptors modulate cardiac spinal afferent nerve activity during myocardial ischemia by suppressing the responses of cardiac afferent nerve to ischemic mediators like bradykinin and extracellular ATP. The nerve activity of single unit cardiac afferents was recorded from the left sympathetic chain (T₂-T₅) in anesthetized cats. Forty-three ischemically sensitive afferent nerves (conduction velocity: 0.32-3.90 m/s) with receptive fields in the left and right ventricles were identified. The responses of these afferent nerves to repeat ischemia or ischemic mediators were further studied in the following protocols. First, epicardial administration of naloxone (8 μmol), a nonselective opioid receptor antagonist, enhanced the responses of eight cardiac afferent nerves to recurrent myocardial ischemia by 62%, whereas epicardial application of vehicle (PBS) did not alter the responses of seven other cardiac afferent nerves to ischemia. Second, naloxone applied to the epicardial surface facilitated the responses of seven cardiac afferent nerves to epicardial ATP by 76%. Third, administration of naloxone enhanced the responses of seven other afferent nerves to bradykinin by 85%. In contrast, in the absence of naloxone, cardiac afferent nerves consistently responded to repeated application of ATP (n = 7) or bradykinin (n = 7). These data suggest that peripheral opioid peptides suppress the responses of cardiac sympathetic afferent nerves to myocardial ischemia and ischemic mediators like ATP and bradykinin.

Keywords: myocardial ischemia; naloxone; opioid receptors; sympathetic afferent nerves.

Fig. 1.

Diagrammatic graph showing the location of the receptive fields of 43 ischemically sensitive cardiac afferent nerves on the epicardial surface of the left (n = 41) and right (n = 2) ventricles. The following protocols included receptive fields of cardiac afferent nerves in the study: ischemia + naloxone (○; n = 8), repeat ischemia (☐; n = 7), ATP + naloxone (★; n = 7), repeat ATP (■; n = 7), bradykinin (BK) + naloxone (●; n = 7), and repeat BK (▲; n = 7).

Fig. 2.

Effect of opioid receptor blockade with the specific antagonist naloxone on ischemia-mediated responses of a left ventricular afferent nerve [anterior wall, conduction velocity (CV) = 0.45 m/s]. Before blockade (A), the afferent nerve response increased from 0.23 to 3.83 impulses/s (imp/s) during ischemia. After blockade (B), the C-fiber response to repeat ischemia was enhanced by 39%. Neurograms 1–4 are representative tracings of afferent nerve responses at the times shown by the arrows in the histograms.

Fig. 3.

A: bar graph showing changes in activity of eight cardiac sympathetic afferent nerves before (open bars) and during (solid bars) 5 min of repeated myocardial ischemia before (−) and after (+) treatment with naloxone. B: consistent responses of seven other afferents nerves to myocardial ischemia before and after the administration of vehicle (saline). Values are means ± SE. *P < 0.05 compared with control; #P < 0.05, postnaloxone vs. prenaloxone.

Fig. 4.

Effect of opioid receptor blockade with naloxone on responses of left ventricular afferent nerves (posterior wall, CV = 0.63 m/s) to epicardial application of ATP. Before blockade (A), the cardiac afferent response to epicardial ATP increased from 0.38 to 2.0 imp/s. After blockade (B), the response to ATP was facilitated (0.46 to 3.72 imp/s). Neurograms 1 and 2 are representative tracings of afferent nerve responses at the times shown by lines in the histograms.

Fig. 5.

A: responses of seven cardiac spinal afferent nerves to epicardial application of ATP before and after local treatment with naloxone. B: reproducibility of responses in seven other cardiac afferents to ATP. Values are means ± SE. *P < 0.05 compared with control; #P < 0.05, postnaloxone vs. prenaloxone.

Fig. 6.

A: neurohistograms showing responses of left ventricular afferent nerves (posterior wall, CV = 0.55 m/s) to epicardial application of BK before (1) and after (2) treatment with naloxone. B: responses of seven cardiac sympathetic afferents to epicardial application of BK before and after treatment with naloxone. C: consistent responses of seven other cardiac afferent nerves to BK. Values are means ± SE. *P < 0.05 compared with control; #P < 0.05 postnaloxone vs. prenaloxone.