Metabotropic glutamate receptor 5 antagonism with fenobam: examination of analgesic tolerance and side effect profile in mice.
BACKGROUND
The metabotropic glutamate receptor 5 noncompetitive antagonist fenobam is analgesic in rodents. Future development of fenobam as an analgesic in humans will require a favorable long-term treatment profile and a lack of significant deleterious side effects. This study aimed to determine whether tolerance to fenobam's analgesic effects developed over 14 days and to assess for side effects in mice.


METHODS
Mouse models of pain, locomotor behavior, and coordination were used. Fenobam or vehicle (n = 8 or 11 per group) was administered for 14 days, and analgesic tolerance to fenobam was assessed using the formalin test. Histopathologic examination, hematology, and clinical chemistry analysis after 14-day fenobam administration were also assessed (n = 12 or 9). The effects of fenobam on locomotor activity were assessed in the open field and elevated zero maze (n = 8 or 7). Coordination was assessed using ledge crossing and vertical pole descent tasks (n = 11 or 10).


RESULTS
Tolerance to fenobam's analgesic effect did not develop after 14 days. Chronic fenobam administration resulted in statistically significantly less weight gain compared with vehicle control subjects, but did not cause any physiologically or statistically significant hematologic abnormalities, altered organ function, or abnormal histopathology of the liver, brain, or testes. Fenobam administration resulted in a metabotropic glutamate receptor 5-dependent increase in exploratory behavior but does not impair motor coordination at analgesic doses.


CONCLUSIONS
Analgesic tolerance to repeat fenobam dosing does not develop. Chronic dosing of up to 14 days is well tolerated. Fenobam represents a promising candidate for the treatment of human pain conditions.
Medical Scientist Training Program, Department of Anesthesiology, Washington University Pain Center, Program in Neuroscience, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Michael C
MC
Montana
Beth A
BA
Conrardy
Laura F
LF
Cavallone
Benedict J
BJ
Kolber
Lesley K
LK
Rao
Suellen C
SC
Greco
Robert W
RW
Gereau
D000700:Analgesics / Q000097:blood / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004435:Eating / Q000187:drug effects; D007093:Imidazoles / Q000097:blood / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D015430:Weight Gain / Q000187:drug effects
D000700:Analgesics; D007093:Imidazoles; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C032794:fenobam