We previously showed that
isovaline is a peripheral
analgesic which acts in vivo and in brain slices as an atypical metabotropic
GABA(B) agonist. Peripheral inhibitory group II and III
metabotropic glutamate receptors (mGluRs) belong to the same family C as
GABA(B) receptors; therefore, we hypothesized that
isovaline's
analgesic effects could include their activation. We examined the effects of R-
isovaline on
mechanical allodynia produced by
prostaglandin E2 in the mouse paw. Subcutaneous R-
isovaline produced dose-dependent antiallodynia restricted to the injected hindlimb. This antiallodynia was blocked by co-injection with a selective group II mGluR antagonist,
LY341495, but not a group III mGluR antagonist (MAP-4). The antiallodynic effect of R-
isovaline was potentiated by co-administration of a group II mGluR-positive allosteric modulator,
LY487379. Injection of a group II mGluR agonist (
LY354740) produced an antiallodynic effect which was completely reversed by group II antagonism, but was not affected by group III or
GABA(B) (CGP35348) antagonism. Similarly, group II mGluR antagonism did not alter the antiallodynia produced by the prototypical
GABA(B) agonist,
baclofen. Hence, there was no apparent crosstalk between group II mGluRs and
GABA(B) receptors. Previous studies have demonstrated that peripheral
GABA(B) receptor activation by
isovaline produces antiallodynia. In addition, the present results indicate that activation of peripheral group II mGluRs by R-
isovaline produces antiallodynia.