Orphanin FQ inhibits capsaicin-induced thermal nociception in monkeys by activation of peripheral ORL1 receptors

Abstract

1. Orphanin FQ (OFQ), an endogenous peptide for ORL1 receptors, has been identified. Although the actions of OFQ have much in common with those of opioid peptides at the cellular level, behavioral studies in rodents seem conflicting. 2. The aim of this study was to investigate the potential pronociceptive or antinociceptive function of peripheral ORL1 receptors in primates. Experiments were conducted to verify whether local administration of OFQ can attenuate capsaicin-induced nociception and whether peripheral ORL1 receptors selectively mediate the local action of OFQ in monkeys. 3. Capsaicin (100 microg) was administered subcutaneously in the tail to locally evoke a nociceptive response (thermal allodynia/hyperalgesia), which was manifested as a reduced tail-withdrawal latency in normally innocuous 46 degreeC warm water. 4. Co-administration of OFQ (1--30 microg) with capsaicin in the tail dose-dependently inhibited thermal nociception. However, a locally effective dose of OFQ (30 microg), when applied in the back, did not inhibit capsaicin-induced nociception. 5. OFQ-induced local antinociception was antagonized by a small dose (10 microg) of J-113397, a selective ORL1 receptor antagonist, in the tail. Similarly, s.c. administration of 10 microg of J-113397 in the back did not antagonize local antinociception of OFQ. 6. In addition, s.c. administration of either OFQ or J-113397 in the tail alone did not change its thermal nociceptive threshold. Local administration of opioid receptor antagonists selective for mu, kappa, and delta opioid receptors did not antagonize OFQ-induced local antinociception. Local administration of J-113397 also did not interfere with the local actions of mu, kappa, and delta opioid agonists in the tail. 7. These results provide the first functional evidence that activation of peripheral ORL1 receptors produces thermal antinociception in primates and this action is independent of antinociception produced at classical opioid receptors.

Figure 1

Time course of capsaicin-induced thermal nociception, allodynia/hyperalgesia, in monkeys. Each panel represents the time course of capsaicin effect on the tail-withdrawal latency in different degrees of water. All points represent the mean±s.e.m. (n=6). Before injection, the tail-withdrawal latencies were determined. Either capsaicin 100 μg or vehicle solution was injected subcutaneously in the tail with constant 0.1 ml volume at ‘0' time point.

Figure 2

Antinociceptive effects of orphanin FQ against capsaicin-induced thermal nociception in 46°C water. Filled gray bars indicate that orphanin FQ was co-administered with capsaicin (100 μg) in the tail and black bars indicate that orphanin FQ was administered s.c. in the back. Each value represents the mean±s.e.m. (n=6). Asterisks represent a significant difference from control, i.e., capsaicin alone (**P<.01). Abscissae: doses of orphanin FQ. Ordinates: tail-withdrawal latency (s). Each data point was obtained at 15 min after injection. See Methods for other details.

Figure 3

Antagonism of J-113397 in local antinociceptive effects of orphanin FQ in 46°C water. CTRL represents the effects of co-administration of capsaicin 100 μg and orphanin FQ 30 μg in the tail. J-113397 was co-administered with capsaicin and orphanin FQ in the tail. Asterisks represent a significant difference from CTRL (**P<.01). See Methods and Figure 2 for other details.

Figure 4

The thermal threshold of monkeys exposed to warm water in the absence and presence of either orphanin FQ or J-113397 in the tail. Open symbols represent tail-withdrawal latencies following s.c. administration of either orphanin FQ or J-113397 in the tail. Not all of the data are shown for the sake of clarity. See Methods and Results for other details.

Figure 5

Selectivity of orphanin FQ-induced attenuation of capsaicin-induced thermal nociception in 46°C water. CTRL represents the effects of co-administration of capsaicin 100 μg and orphanin FQ 30 μg in the tail. Quadzocine (32 μg), nor-binaltorphimine (nor-BNI, 320 μg), naltrindole (320 μg), or J-113397 (10 μg) was co-administered with capsaicin and orphanin FQ in the tail. Asterisks represent a significant difference from CTRL (**P<.01). See Methods and Figure 2 for other details.

Figure 6

Lack of antagonism by J-113397 against classical opioid agonist-induced local attenuation of capsaicin-induced thermal nociception in 46°C water. The symbol ‘T' indicates the corresponding compound was administered subcutaneously in the tail. The symbol ‘ – ' indicates the corresponding compound was not given in the tail. Different shaded columns are paired to compare the antagonist effect of J-113397 (10 μg) against the actions of μOR agonist (DAMGO, 32 μg), κOR agonist (U50488, 100 μg), and δOR agonist (BW373U86, 320 μg), respectively. See Methods and Figure 2 for other details.