Effects of naloxone on hemodynamic and sympathetic nerve responses to pain in normotensive vs. borderline hypertensive men

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Abstract

Pain sensitivity decreases with increasing resting blood pressure. This blood pressure–pain interaction may be mediated by endogenous opioids which have been shown to affect both blood pressure and nociception. To test this hypothesis, we measured mean arterial blood pressure (MAP), central venous pressure (CVP), heart rate (HR), muscle sympathetic nerve activity (MSNA), serum catecholamines, and individual pain rating scales during 2 min periods of noxious mechanostimulation (skin fold pinching) in nine young (26±2 year), male normotensive (NT) subjects and in 12 age and weight matched males with borderline hypertension (BHT). Measurements were performed before and after the i.v. administration of naloxone (0.15 mg/kg) and placebo in a randomized double-blind cross-over trial. In the pre-naloxone trials, pain led to similar changes in MAP, CVP, MSNA and plasma catecholamines in the two groups except for a higher increase in HR in the BHT group as compared to the NT group (3±1 vs. 1±1 bpm; P<0.005). Opioid blockade with naloxone increased MSNA responses to pain in the NT group (from 5±1 to 9±1 bursts/min, and, from 100±23 to 204±36 units/min, respectively; P<0.05) but did not significantly affect the MSNA response to pain in the BHT group. Pain induced responses of MAP, CVP, and catecholamines were not altered by naloxone in either group. Overall, there was a highly significant inverse correlation between pain perception and resting blood pressure which was not significantly affected by naloxone. The BHT subjects exhibited a lower pain perception compared to the NT subjects (P<0.005). Naloxone increased pain rating in the NT group (from 194±9 to 218±13; P<0.005) but not in the borderline hypertensive group (160±8 vs. 168±10; P=0.36). Except for a decreased HR response in the BHT group, placebo had no effect on the responses to pain. Our data do not indicate a major role of the endogenous opioid system for the blood pressure–pain interaction in man. Endogenous opioids affect pain perception and sympathetic nerve activity responses to pain in normotensive men but their activity seems to be attenuated in borderline hypertensive subjects. Therefore, the lower pain sensitivity in human essential hypertension is probably mediated by non-opioid mechanisms.

Introduction

In humans, increased levels of blood pressure are associated with a diminished perception of pain. Several investigators (Zamir and Shuber, 1980; Ghione et al., 1988; Sheps et al., 1992) have found higher pain thresholds in hypertensive as compared to normotensive subjects. The interaction between blood pressure and pain sensitivity may be mediated via the effects of endogenous opioids on both blood pressure and nociception (Randich and Maixner, 1984; France et al., 1991; Maixner, 1991). Animal research indicates that genetically hypertensive rats and rats with experimentally induced hypertension both exhibit a decreased pain sensitivity, which can be normalized by the opioid antagonist naloxone. Naloxone under the conditions tested had no effect in normotensive control animals (Zamir and Segal, 1979; Zamir et al., 1980; Saavedra, 1981; Maixner et al., 1982; Sitsen and de Jong, 1984). These data indicate that chronic elevation of blood pressure may activate endogenous pain-inhibitory systems. This mechanism may be part of an adaptive response of the body to stressful events. A causative role of the endogenous opioid system for the observed association between hypertension and increased pain tolerance is suggested, not only by the naloxone-induced antagonism of this hypoalgesia in animals, but also by the findings of elevated levels of endogenous opioids in hypertension-prone Sabra-rats, hypertensive Goldblatt-rats, and spontaneously hypertensive (SHR) rats (Zamir et al., 1980). A recent study in humans by Sheps et al. (1992)showed an increased pain tolerance and higher plasma beta-endorphin levels in hypertensive patients, compared to normotensive subjects. However, these investigators did not observe a significant inverse relationship between pain perception and circulating endorphin levels.

To further clarify the role of the endogenous opioid system for the interaction between blood pressure and pain regulatory systems in humans, we examined the effects of naloxone on the changes in arterial and central venous blood pressure, heart rate, muscle sympathetic nerve activity (MSNA, representing sympathetic vasoconstrictor activity), serum catecholamines, and individual pain perception rating during noxious mechano-stimulation in normotensive and in borderline hypertensive subjects. To test whether or not elevated levels of endogenous opioids participate in the hypoalgesia seen in human hypertension, the hemodynamic and sympathetic responses before and after naloxone were compared to the responses seen before and after placebo on a different day, in a randomized double-blind cross-over fashion.

Section snippets

Subjects

Included in this study were 21 white male subjects. Twelve subjects had borderline hypertension and nine subjects were normotensive. The volunteers were matched with regard to age (25±2 vs. 26±2 year, P=NS), weight (78±11 vs. 80±12 kg, P=NS), and body mass index (24.1±2.2 vs. 24.4±2.1 kg/m2, P=NS). All subjects were recruited from the University of Erlangen–Nürnberg campus and were studied before and after administration of the opioid antagonist naloxone and placebo on 2 different days (range:

Baseline measures of hemodynamic and sympathetic activity data

Table 1 compares all variables at baseline (i.e. before the application of pain) during all drug conditions between the two study groups. The borderline hypertensive subjects had higher baseline levels of mean arterial pressure and heart rate as compared to the normotensive subjects but did not differ from the normotensive subjects with regard to central venous pressure, MSNA or plasma catecholamines (Table 1). Administration of naloxone and placebo did not significantly alter the pre-drug

Discussion

Overall, we found a significant inverse correlation between resting blood pressure and pain perception, and the borderline hypertensive group exhibited a lower pain sensitivity as compared to the normotensive control group. The major new findings of the present study is, however, that pain rating and sympathetic nerve responses to pain were increased after opioid blockade with naloxone in the normotensive but not in the borderline hypertensive subjects. Pain induced responses of arterial

Conclusion

This study provides evidence suggesting that endogenous opioids do not determine the interaction between blood pressure and pain perception in men. Moreover, our data suggest that pain induced activation of the endogenous opioid system seems to be attenuated in borderline hypertensive men, indicating that the lower pain sensitivity in human hypertension may be mediated by non-opioid mechanisms. Future studies are needed to further define the relationships among non-opioid antinociceptive

Acknowledgements

These studies were supported by a grant in aid to HPS (Scho 398/3-1) from the Deutsche Forschungsgemeinschaft.

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