Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995. The generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of nociceptin. In addition, radio-imaging technologies have been advanced for investigation of this system in animals and humans. Together with traditional neurobehavioral techniques, these tools have been utilized to identify the biological significance of the N/OFQ system and its interacting partners. The present commentary focuses on the role of N/OFQ in the regulation of feeding and body weight homeostasis, stress and the stress-related psychiatric disorders of depression and anxiety, and in drug and alcohol dependence. Critical evaluation of the current scientific preclinical literature suggests that small molecule modulators of nociceptin opioid peptide receptors (NOP) might be useful in the treatment of diseases related to these biological functions. In particular, the literature data suggest that antagonism of NOP receptors will produce anti-obesity and antidepressant activities in humans. However, there are also contradictory data discussed. The current literature on the role of N/OFQ in anxiety and addiction, on the other hand points primarily to a role of agonist modulation being potentially therapeutic. Some drug-like molecules that function either as agonists or antagonists of NOP receptors have been optimized for human clinical study to test some of these hypotheses. The discovery of PET ligands for NOP receptors, combined with the pharmacological tools and burgeoning preclinical data set discussed here bodes well for a rapid advancement of clinical understanding and potential therapeutic benefit.

1 The endogenous cannabinoid agonist, anandamide produced a modest contractile response in guinea-pig isolated bronchus compared with the vanilloid receptor agonist capsaicin. The contractile response to both anandamide and capsaicin was inhibited by the vanilloid receptor antagonist, capsazepine. Furthermore, the NK 2 -selective antagonist, SR48968 but not the NK 1 -selective antagonist, SR140333 inhibited contractile responses to anandamide. 2 The contractile response to anandamide was abolished in tissues desensitized by capsaicin. However, anandamide failed to cross-desensitize the contractile response to capsaicin. 3 The contractile response to anandamide was not signi®cantly altered in the presence of the CB 1 receptor antagonist, SR141716A, nor the amidase inhibitor, phenylmethylsulphonyl¯uoride (PMSF) but was signi®cantly increased in the presence of the neutral endopeptidase inhibitor, thiorphan. 4 The cannabinoid agonist, CP55,940 failed to signi®cantly attenuate the excitatory non-adrenergic non-cholinergic (eNANC) response in guinea-pig airways. In contrast, the ORL 1 receptor agonist, nociceptin, signi®cantly inhibited this response. 5 The results demonstrate that anandamide induces a modest contractile response in guinea-pig isolated bronchus that is dependent upon the activation of vanilloid receptors on airway sensory nerves. However, cannabinoid receptors do not appear to play a role in this regard, nor in regulating the release of neuropeptides from airway sensory nerves under physiological conditions.

This study examined differences between long-term exercising (LE) and long-term nonexercising (LNE) women [n = 24; age 56.4 +/- 6.2 (SD) yr] for resting metabolic rate (RMR) and energy expenditure in the free-living state by using doubly labeled water (DLW). There was a statistically significant difference (P = 0.0002) between the 12 LE (94.85 +/- 8.44 kJ . kg-1 . day-1) and 12 LNE (81.16 +/- 6.62 kJ . kg-1 . day-1) for RMR, but this difference was only marginally significant (P = 0.06) when the data (MJ/day) were subjected to an analysis of covariance with fat-free mass as the covariate. The DLW data indicated that the eight most active LE (12.99 +/- 3.58 MJ/day) expended significantly (P = 0.01) more energy than did the eight least active LNE (9.30 +/- 1.15 MJ/day). Energy expenditures ranged from 7.64 to 18.15 MJ/day, but there was no difference (P = 0.96) between the LE and LNE in energy expenditure during activity that was not designed to either improve or maintain fitness. These cross-sectional data on 49- to 70-yr-old women therefore suggest that 1) aerobic-type training results in a greater RMR per unit of body mass and also when statistical control is exerted for the effect of the metabolically active fat-free mass, 2) there is a large range in the energy intake necessary to maintain energy balance, and 3) aerobic training does not result in a compensatory reduction in energy expenditure during the remainder of the day.