Repeated dosing with oral allosteric modulator of adenosine A1 receptor produces tolerance in rats with neuropathic pain.
BACKGROUND
The positive allosteric adenosine receptor modulator, T62 (2-amino-3-(4-chlorobenzoyl)-5,6,7,8-tetrahydrobenzothiophene), has been shown to reduce mechanical allodynia in a rat model of neuropathic pain. However, whether chronic oral T62 retains efficacy in this pain model has not been examined. Therefore, the authors studied antiallodynic effects of chronic oral T62 in spinal nerved-ligated rats, as well as motor and sedative behavioral effects.


METHODS
Oral T62, 100 mg/kg, or oral oil was applied daily to spinal nerve-ligated rats for 4 weeks, with rat weights examined daily. Sedation, placing and ambulation scores, and withdrawal threshold were observed for 3 h daily for the first 2 weeks and then once a week. At the end of observation, the animals were killed, and the spinal tissues were collected for radioligand binding. In addition, withdrawal thresholds were also observed in rats with 5 days of treatment with 50 mg/kg oral T62. Furthermore, the effects of intrathecal adenosine on rats with oral T62 or oil treatment were compared.


RESULTS
Chronic oral T62, at 100 mg/kg, initially returned the withdrawal threshold to mechanical testing to preinjury levels, with minor or no sedative or motor effects. Tolerance was observed, with a 60% loss of most possible effects in antiallodynia within 5 days of daily administration. Similarly, tolerance also occurred with chronic oral T62 at 50 mg/kg but did not alter the effect of intrathecal adenosine. Furthermore, 4 weeks of exposure to 100 mg/kg T62 resulted in a small reduction in spinal cord A1 receptor number.


CONCLUSIONS
The results imply that chronically administered A1 adenosine modulators lose efficacy over time, partly as a result of receptor down-regulation.
Li
Xinhui
X
Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. xli@wfubmc.edu
Bantel
Carsten
C
Conklin
Dawn
D
Childers
Steven R
SR
Eisenach
James C
JC
D000241:Adenosine / Q000494:pharmacology; D000284:Administration, Oral; D000494:Allosteric Regulation; D000818:Animals; D004361:Drug Tolerance; D008297:Male; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000187:drug effects* / Q000502:physiology; D013127:Spinal Nerves / Q000293:injuries; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*; D014970:Xanthines / Q000378:metabolism
C475229:2-amino-3-(4-chlorobenzoyl)-5,6,7,8-tetrahydrobenzothiophene; D043682:Receptor, Adenosine A1; D013876:Thiophenes; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine