Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans

Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the μ-OR sub-type. In a sample of healthy volunteers, we used [11C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4–100 mg) or NTX (range, 2–50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50=7.10 ng ml−1) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-β-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration–RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption

Deletion of the M(5) muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia

Little is known about the physiological roles of the M(5) muscarinic receptor, the last member of the muscarinic receptor family (M(1)–M(5)) to be cloned. In the brain, the M(5) receptor subtype is preferentially expressed by dopaminergic neurons of the substantia nigra and the ventral tegmental area. Dopaminergic neurons located in the ventral tegmental area are known to play important roles in mediating both the rewarding effects of opiates and other drugs of abuse and the manifestations of opiate/drug withdrawal symptoms. We therefore speculated that acetylcholine-dependent activation of M(5) receptors might modulate the manifestations of opiate reward and withdrawal. This hypothesis was tested in a series of behavioral, biochemical, and neurochemical studies using M(5) receptor-deficient mice (M(5)(−/−) mice) as novel experimental tools. We found that the rewarding effects of morphine, as measured in the conditioned place preference paradigm, were substantially reduced in M(5)(−/−) mice. Furthermore, both the somatic and affective components of naloxone-induced morphine withdrawal symptoms were significantly attenuated in M(5)(−/−) mice. In contrast, the analgesic efficacy of morphine and the development of tolerance to the analgesic effects of morphine remained unaltered by the lack of M(5) receptors. The finding that M(5) receptor activity modulates both morphine reward and withdrawal processes suggests that M(5) receptors may represent a novel target for the treatment of opiate addiction