The role of peripheral mu opioid receptors in the modulation of capsaicin-induced thermal nociception in rhesus monkeys

Abstract

Capsaicin produces burning pain, followed by nociceptive responses, such as allodynia and hyperalgesia in humans and rodents. In the present study, when administered subcutaneously into the tail of rhesus monkeys, capsaicin (0.01-0.32 mg) dose-dependently produced thermal allodynia manifested as reduced tail-withdrawal latencies in 46 degrees C water, from a maximum value of 20 sec to approximately 2 sec. Coadministration of selective mu opioid agonists, fentanyl (0.003-0.1 mg) and (D-Ala2,N-Me-Phe4, Gly5-ol)-enkephalin (0.001-0.03 mg), dose-dependently inhibited capsaicin-induced allodynia. This local antinociception was antagonized by small doses of opioid antagonists, quadazocine (0.03 mg) and quaternary naltrexone (1 mg), applied locally in the tail. However, these doses of antagonists injected s.c. in the back did not antagonize local fentanyl. Comparing the relative potency of either agonist or antagonist after local and systemic administration confirmed that the site of action of locally applied mu opioid agonists is in the tail. These results provide evidence that activation of peripheral mu opioid receptors can diminish capsaicin-induced allodynia in primates. This experimental pain model could be a useful tool for evaluating peripherally acting antinociceptive agents without central side effects and enhance new approaches to the treatment of inflammatory pain.

Fig. 1

Thermal allodynia caused by capsaicin locally applied in the tail. (Upper panel) temperature-effect curves measured at 15 min after injection. (Lower panel) time course of capsaicin-induced thermal allodynia in 46°C water. All points represent the mean ± S.E.M. (n = 6). Asterisks represent significant difference (P < .01) from vehicle.

Fig. 2

Antinociceptive effects of fentanyl (left panels) and DAMGO (right panels) administered locally (hashed bars, in the tail) or systemically (filled bars, in the back) against 46°C water in the presence of 0.1 mg capsaicin or against 50°C water in the absence of capsaicin. Each value represents the mean ± S.E.M. (n = 3–6). Abscissae (all panels): agonist doses in mg or mg/kg (s.c.). Ordinates (all panels): percent of maximum possible effect (%MPE). Each data point was obtained 15 min after injection. See “Methods” for other details.

Fig. 3

Antagonist effects of quadazocine administered locally (hashed bars, in the tail) and systemically (filled bars, in the back) against local fentanyl in 46°C water in the presence of capsaicin. CTRL represents the effects of coadministration of 0.1 mg of capsaicin and 0.1 mg of fentanyl in the tail. Other details are as in figure 2.

Fig. 4

Antagonist effects of quaternary naltrexone administered locally (hashed bars, in the tail) and systemically (filled bars, in the back) against local fentanyl in 46°C water in the presence of capsaicin. CTRL represents the effects of coadministration of 0.1 mg of capsaicin and 0.1 mg of fentanyl in the tail. Other details are as in figure 2.

Fig. 5

Quadazocine potency in antagonizing systemic fentanyl against either 50°C water without capsaicin or 46°C water in the presence of capsaicin. Open symbols represent dose-effect curves determined alone. Closed symbols represent dose-effect curves obtained 30 min after quadazocine (0.1 mg/kg) pretreatment. All points represent the mean ± S.E.M. (n = 3). Abscissae (all panels): fentanyl dose in mg/kg. Ordinates (all panels): %MPE. Each data point was obtained 15 min after fentanyl injection in a single dosing procedure.