Morphine is an arteriolar vasodilator in man

Abstract

Aim: The mechanisms of action of morphine on the arterial system are not well understood. The aim was to report forearm vascular responses, and their mediation, to intra-arterial morphine in healthy subjects.

Methods: Three separate protocols were performed: (i) dose ranging; (ii) acute tolerance; (iii) randomized crossover mechanistic study on forearm blood flow (FBF) responses to intrabrachial infusion of morphine using venous occlusion plethysmography. Morphine was infused either alone (study 1 and 2), or with an antagonist: naloxone, combined histamine-1 and histamine-2 receptor blockade or during a nitric oxide clamp.

Results: Morphine caused an increase in FBF at doses of 30 microg min(-1)[3.25 (0.26) ml min(-1) 100 ml(-1)][mean (SEM)] doubling at 100 microg min(-1) to 5.23 (0.53) ml min(-1) 100 ml(-1). Acute tolerance was not seen to 50 microg min(-1) morphine, with increased FBF [3.96 (0.35) ml min(-1) 100 ml(-1)] (P = 0.003), throughout the 30-min infusion period. Vasodilatation was abolished by pretreatment with antihistamines (P = 0.008) and the nitric oxide clamp (P < 0.001), but not affected by naloxone. The maximum FBF with pretreatment with combined H1/H2 blockade was 3.06 (0.48) and 2.90 (0.17) ml min(-1) 100 ml(-1) after 30 min, whereas with morphine alone it reached 4.3 (0.89) ml min(-1) 100 ml(-1).

Conclusions: Intra-arterial infusion of morphine into the forearm circulation causes vasodilatation through local histamine-modulated nitric oxide release. Opioid receptor mechanisms need further exploration.

Figure 1

Morphine infusion rate. Effect of intrabrachial infusion of morphine, in incremental doses of 1, 3, 10, 30 and 100 µg min⁻¹ (see text) in six subjects. Post-infusion recovery is shown to 30 min. Treated (•) and control arm (○) are shown (mean and SEM)

Figure 2

Area of flare in response to intrabrachial infusion at incremental doses of morphine at 1–100 µg min⁻¹ ml⁻¹ (see text) in six subjects during the dose ranging study (mean and SEM). Also shown is the offset of flare following cessation of the infusion

Figure 3

Forearm blood flow (FBF, ml min⁻¹ 100 ml⁻¹ forearm volume) in response to a continuous intrabrachial infusion of morphine in eight subjects at 50 µg min⁻¹ ml⁻¹ for 30 min followed by saline infusion alone for a further 60 min. Data are presented as mean and SEM of FBF in infused arm (•) and non-infused arm (○)

Figure 4

Forearm blood flow (FBF, ml 100 ml⁻¹ forearm volume) in response to a continuous 30-min intrabrachial infusion of morphine (80 µg min⁻¹) in eight subjects either alone (○), during co-administration of naloxone (♦), after pretreatment with cetirizine and cimetidine (✗), or in the presence of a nitric oxide clamp (•). The 60-min recovery period is also shown. Data are presented as mean and SEM of FBF in the infused arm

Figure 5

Effects of specific antagonists or no treatment on flare area following continuous intrabrachial morphine infusion (at 80 µg min⁻¹), during the infusion period and for 1 h following it. Morphine alone (○), during co-administration of naloxone (♦), after pretreatment with cetirizine and cimetidine (✗), and in the presence of a nitric oxide clamp (•). All data are mean ± SEM