Antiparkinson potential of delta-opioid receptor agonists.
delta-Opioid receptors, present in very high concentrations in striatum and overlying cortex, are thought to be involved in a number of processes, including analgesia, mood, reward, modulation of neuronal excitability, and alterations in neurotransmitter release. Given the localization of the receptors in motor circuits in brain, we thought it of interest to study the antiparkinson potential of delta-opioid receptor agonists. Rats were given unilateral 6-hydroxydopamine lesions of the nigrostriatal tract, and following recovery, were tested for rotational activity. Tonazocine mesylate is a nonpeptide, partial delta-opioid receptor agonist with mu-receptor antagonist properties. Tonazocine (0.1-10 mg/kg) evoked a dose-related, ipsilateral rotation, consistent with augmentation of dopaminergic function on the unlesioned side. The rotation evoked by tonazocine was blocked by the selective delta-opioid receptor antagonist naltrindole, suggesting that the effect was mediated by delta-opioid receptors. The full delta-opioid receptor agonist (+)-4-¿9-alpha-R)-alpha-(2S,5RO-4-allyl-2, 5-dimethyl-1-piperaziny l)-3-methoxybenzyl-N,N-diethylbenzamide (SNC-80) produced both contralateral and ipsilateral rotation. Tonazocine additionally augmented the effects of L-3,4 dihydroxyphenylalanine (L-DOPA) on reserpine-induced suppression of motor activity. Binding affinities and efficacies of tonazocine and SNC-80 against mu-, kappa-, and delta-opioid receptors were also confirmed and compared to standards. These data suggest therapeutic potential of agents interacting with delta-opioid receptors, and indicate some differences in the activities of tonazocine and SNC-80.
Hudzik
T J
TJ
Department of Pharmacology, AstraZeneca R&D Boston, 3 Biotech, 1 Innovation Dr., Worcester, MA 01605, USA. thomas.hudzik@astrazeneca.com
Howell
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A
Payza
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Cross
A J
AJ
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001392:Azocines / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D017465:Receptors, Opioid, delta / Q000819:agonists*; D012110:Reserpine / Q000494:pharmacology; D012399:Rotation
D000978:Antiparkinson Agents; D001392:Azocines; D001549:Benzamides; D010879:Piperazines; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D012110:Reserpine; C045480:tonazocine