Peripheral µ-opioid receptors attenuate the responses of group III and IV afferents to contraction in rats with simulated peripheral artery disease

Abstract

Patients with peripheral artery disease show an exaggerated pressor response to mild exercise, an effect attributable to the exercise pressor reflex, whose afferent arm comprises the thinly myelinated group III and unmyelinated group IV afferents. Previously, we found that DAMGO, a µ-opioid agonist injected into the femoral artery, attenuated the exaggerated exercise pressor reflex in rats with ligated femoral arteries, a preparation that simulates the blood flow patterns to muscle that is seen in patients with peripheral artery disease. Continuing this line of investigation, we recorded the responses of group III and IV afferents to static contraction before and after injecting DAMGO (1 µg) into the superficial epigastric artery in rats with patent femoral arteries and in rats with ligated femoral arteries. In rats with patent arteries, DAMGO did not change the responses to contraction of either group III ( n = 9; P = 0.83) or group IV ( n = 8; P = 0.34) afferents. In contrast, in rats with ligated femoral arteries, DAMGO injection (1 µg) significantly decreased the responses to contraction of both group III afferents ( n = 9, P < 0.01) and group IV afferents ( n = 9; P < 0.01). DAMGO did not significantly attenuate the responses of either group III or IV afferents to capsaicin in rats with either patent or ligated femoral arteries. These findings are in agreement with our previous studies that showed that peripheral DAMGO injection attenuated the exercise pressor reflex in rats with ligated femoral arteries but had only a modest effect on the exercise pressor reflex in rats with patent femoral arteries. NEW & NOTEWORTHY In an animal model of peripheral artery disease, we show that the µ-opioid agonist, DAMGO reduces the afferent response rate resulting from stimulated static contraction. These results suggest that peripherally active opioid agonists that do not cross the blood-brain barrier may be therapeutic for treatment of peripheral artery disease without the negative and addictive side effects associated with opioids in the central nervous system.

Keywords: DAMGO; autonomic control; exercise pressor reflex; sympathetic nervous system; thin fiber muscle afferents.

Fig. 1.

Individual example of the responses to static contraction of a group IV afferent before and after DAMGO. A and B: histograms showing the responses to contraction of a group IV afferent before (A) and after (B) injecting 1 µg DAMGO into the superficial epigastric artery. Contraction, which lasted for 30 s, was initiated at time zero. C and D: recordings of the impulse activity of the group IV afferent 3 s after the initiation of contraction. Arrowheads signify action potentials. Stimulation artifacts are the large equally spaced vertical lines. Scale bars = 100 ms. Lower case a and b correspond to time points shown in C and D, respectively. Imp, impulses.

Fig. 2.

Summary data showing that the responses to contraction are reduced by DAMGO in group III and IV afferents whose impulse activity was recorded from “ligated” rats, but was not reduced in group III and IV afferents whose impulse activity was recorded from “freely perfused” rats. Black vertical bars represent mean values for the 30 s of control preceding contraction, whereas gray vertical bars represent mean values for the 30 s of contraction. Vertical brackets over each bar represent the standard error of the mean, whereas horizontal brackets represent significant differences between before and after DAMGO injection (1 µg) into the superficial epigastric artery. **P < 0.01, ***P < 0.001 vs. contraction for same condition.

Fig. 3.

Second-by-second plots of the effect of DAMGO on the summed activity of the group III and IV afferents responsive to contraction. Open circles represent summed activity before injecting DAMGO, whereas closed squares represent summed activity after injecting 1 µg DAMGO into the superficial epigastric artery. “Freely perfused” rats show similar discharge rates for group III (A) and group IV (C) afferents before and after DAMGO. “Ligated” rats show reduced discharge rates for both group III (B) and group IV (D) afferents.

Fig. 4.

Summary data showing that the responses to capsaicin of group III and IV afferents were not reduced by DAMGO in either “freely perfused” or “ligated rats.” Black vertical bars represent mean values for the 30 s of control preceding capsaicin injection, whereas the gray vertical bars represent mean values for the 30 s following capsaicin (0.2 µg) injection into the superficial epigastric artery. Vertical brackets over each bar represent the standard error of the mean. Injecting DAMGO (1 µg) into the superficial epigastric artery did not significantly change the response in afferent fibers from freely perfused (A, B) or ligated (C, D) rats. *P < 0.05, **P < 0.01, ***P < 0.001 vs. capsaicin for same condition.