Analgesic effects of the selective group II (mGlu2/3) metabotropic glutamate receptor agonists LY379268 and LY389795 in persistent and inflammatory pain models after acute and repeated dosing.
Group II (mGluR2/3) metabotropic glutamate receptors have been implicated in the mechanisms of persistent pain states. In the present study, the effects of the selective group II metabotropic glutamate receptor agonists LY379268 and LY389795 were evaluated in the formalin test, carrageenan-induced thermal hyperalgesia and mechanical allodynia, and capsaicin-induced mechanical allodynia in rats. The agonists LY379268 and LY389795 produced dose-dependent decreases in formalin-induced behaviors that were antagonized by the mGlu2/3 receptor antagonist LY341495. The group II antagonist LY341495 produced parallel shifts in the LY379268 dose-response curve, consistent with a competitive antagonism. LY379268 decreased formalin-induced behaviors after intracisternal but not intrathecal administration, suggesting primarily a supraspinal site of action. Both LY379268 and LY389795 produced a dose-related reversal of carrageenan-induced thermal hyperalgesia and capsaicin-induced mechanical allodynia, but had no effect on carrageenan-induced mechanical allodynia. Both agonists also increased response latencies in the hot plate test, but were without effect in the tail-flick test. However, both agonists produced motor impairment on the inverted screen at doses that were analgesic. Moreover, tolerance to the analgesic effects of LY379268 developed after 4 days of once-daily repeated administration in the formalin, carrageenan, capsaicin and hot plate tests. The present findings indicate that group II (mGluR2/3) metabotropic glutamate receptors may be involved in the mechanisms of hyperalgesia and allodynia, however tolerance rapidly develops to these effects.
Jones
Carrie K
CK
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Eberle
Elizabeth Lutz
EL
Peters
Stephen C
SC
Monn
James A
JA
Shannon
Harlan E
HE
D000596:Amino Acids / Q000008:administration & dosage*; D000700:Analgesics / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D006987:Hypesthesia / Q000188:drug therapy / Q000209:etiology; D007249:Inflammation / Q000150:complications / Q000188:drug therapy; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013997:Time Factors
D000596:Amino Acids; D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; C118219:LY 389795; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2