The 46°C water was the thermal threshold for these subjects for expressing allodynic responses following the local injection of the capsaicin (Ko , 1998b, 2002b). in the tail, it dose-dependently produced thermal allodynia that peaked 15 min following the injection.

The studies were conducted in accordance with the University Committee on the Use and Care of Animals at the University of Michigan and the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the US National Institutes of Health (National Academy Press, Washington DC, revised 1996)., 1998a).

Briefly, monkeys were seated in primate restraint chairs, and the lower part of their shaved tails (approximately 15 cm) were immersed in a thermal flask containing water maintained at either 42, 46, or 50°C.

In particular, the self-administration assay in monkeys has been used extensively, and it provides useful information for the abuse liability of drugs in humans (Weerts -opioid agonists produce reinforcing effects, drugs in these categories do not have promising pharmacological profiles as strong analgesics because of their undesirable side effects. An endogenous peptide selective for the NOP receptor, nociceptin/orphanin FQ (N/OFQ), has been identified and shown to have similar actions as other opioid peptides at the cellular level (Meunier , 2005).

Interestingly, both peripheral and spinal administration of N/OFQ produce antinociceptive effects in monkeys, indicating a potential therapeutic value of NOP receptor agonists as analgesics (Ko , 2007; Shoblock, 2007).

Opioid analgesics are the most effective and widely used drugs for pain management; the most clinically used opioids are μ-opioid receptor agonists (Zollner and Stein, 2007).

However, there are several side effects associated with the use of μ-opioid agonists.The NOP receptor antagonist potency of J-113397 against Ro 64-6198-induced antinociception was determined by giving subjects different doses of s.c. A single dose of naltrexone (0.03 mg/kg) and J-113397 (0.1 mg/kg) was used to compare their antagonist effects against both alfentanil- and Ro 64-6198-induced antinociception.The dose and pretreatment time (ie, 15 min) for both naltrexone and J-113397 were chosen based on an earlier study (Ko , 1998b, 2002b).These include constipation, respiratory depression, and itch/pruritus (Zollner and Stein, 2007).Importantly, the abuse liability derived from μ-opioid agonists has been and remains a serious public health concern and limits the opioid analgesics' value for pain management (Cicero , 2007).Then, the test compound was administered subcutaneously by a cumulative dosing procedure with a 30-min interinjection interval.