Abstract：
:Identification of synthetic agonists and antagonists at orphan receptors represents an important step for understanding their physiological function and therapeutic potential. Accordingly, we have recently described a non-peptide agonist at the opioid receptor like (ORL1) receptor (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro64-6198; Jenck et al., PNAS 94 (2000) 4938; Wichmann et al., Eur. J. Med. Chem. 35 (2000) 839). We have investigated the effects of this compound in various tests of rodent neurological function, utilising ORL1 knockout mice to examine the pharmacological specificity of Ro64-6198. In male C57BL/6J mice, effects on balance and motor co-ordination were detected following low doses (0.3-1mg/kg IP) of Ro64-6198. At higher doses (1-3mg/kg IP), effects on swim behaviour and hypothermia was observed. At 10mg/kg, each effect became more profound and a severe neurological disturbance appeared, including loss of righting reflex. These effects of Ro64-6198 (10mg/kg IP) were absent in ORL1 receptor knockout mice. In male, hooded Lister rats, Ro64-6198 (6-10mg/kg IP), produced some disturbance of neurological function, including hypoactivity, rotarod performance, grip strength and mild hypothermia. An impairment of food responding under a variable interval (VI) 20s schedule of reinforcement was noted at 3mg/kg. These results confirm Ro64-6198 to be a highly selective pharmacological tool to investigate ORL1 receptor function in vivo and, furthermore, that activation of this receptor is accompanied by a variety of effects on neurological function.
journal_name
Neuropharmacologyjournal_title
Neuropharmacologyauthors
Higgins GA,Grottick AJ,Ballard TM,Richards JG,Messer J,Takeshima H,Pauly-Evers M,Jenck F,Adam G,Wichmann Jdoi
10.1016/s0028-3908(01)00048-xsubject
Has Abstractpub_date
2001-07-01 00:00:00pages
97-107issue
1eissn
0028-3908issn
1873-7064pii
S002839080100048Xjournal_volume
41pub_type
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