Gabapentin and
pregabalin have been demonstrated, both in animal
pain models and clinically, to be effective
analgesics particularly for the treatment of
neuropathic pain. The precise mechanism of action for these two drugs is unknown, but they are generally believed to function via initially binding to the alpha2delta subunit of voltage-gated Ca2+ channels. In this study, we used a pharmacological approach to test the hypothesis whether high affinity interactions with the alpha2delta subunit alone could lead to attenuation of
neuropathic pain in rats. The anti-allodynic effects of
gabapentin and
pregabalin, along with three other compounds--(
L)-phenylglycine, m-chlorophenylglycine and 3-exo-aminobicyclo[2.2.1]
heptane-2-exo-
carboxylic acid (ABHCA)--discovered to be potent alpha2delta
ligands, were tested in the rat spinal nerve
ligation model of
neuropathic pain.
Gabapentin (Ki = 120 nM),
pregabalin (180 nM) and (
L)-phenylglycine (180 nM) were shown to be anti-allodynic, with respective ED50 values of 230, 90 and 80 micromol/kg (p.o.). (
L)-Phenylglycine was as potent as
pregabalin and equi-efficacious in reversing
mechanical allodynia. In contrast, two
ligands with comparable or superior alpha2delta binding affinities, m-chlorophenylglycine (Ki = 54 nM) and ABHCA (150 nM), exhibited no anti-allodynic effects at doses of 30-300 micromol/kg (p.o.), although these compounds achieved substantial brain levels. The data demonstrate that, at least in the rat spinal nerve
ligation model of
neuropathic pain, (
L)-phenylglycine has an anti-allodynic effect, but two equally potent alpha2delta subunit
ligands do not. These results suggest that additional mechanisms, besides alpha2delta interactions, may contribute to the effects of compounds like
gabapentin,
pregabalin and (
L)-phenylglycine in
neuropathic pain.