Pharmacological comparison of anticonvulsant drugs in animal models of persistent pain and anxiety

Abstract

Signs and symptoms of persistent pain are associated with neuronal hyperexcitability within nociceptive pathways. This manifests behaviourally as a decrease in the nociceptive threshold to sensory stimulation, and is closely correlated with altered affective pain processing and increased expression of anxiety-like symptoms. Anticonvulsant drugs can have marked analgesic actions in animals and humans, and some have also been reported to possess anxiolytic-like properties in animals. In the current study, we have compared the antinociceptive actions of diazepam (allosteric GABA A receptor modulator), gabapentin (binds to α 2δ Ca 2+ channel subunit), lamotrigine, riluzole and phenytoin (Na + channel blockers), levetiracetam (unknown mechanism), sodium valproate (potentiates GABA-mediated inhibition), ethosuximide (T-type Ca 2+ channel blocker) and retigabine (K v7 channel opener) in the rat formalin test, with their anxiolytic actions in the rat conditioned emotional response (CER) model of anxiety. Lamotrigine, gabapentin, riluzole, retigabine and ethosuximide attenuated second phase nociceptive responses in the formalin test. Lamotrigine, gabapentin and riluzole also displayed an anxiolytic-like profile in the CER model. Notably, the minimum doses of these drugs required to attenuate anxiety behaviour were similar to, or considerably lower than those needed to reverse pain-like behaviours. Diazepam was anxiolytic but only attenuated pain-like behaviours at sedative doses. The other drugs tested were inactive in both models. Our data suggests: (i) an antiepileptic mechanism of action per se is not necessarily sufficient for a compound to display antinociceptive and/or anxiolytic actions; and (ii) the combined antinociceptive and anxiolytic-like profiles of lamotrigine, gabapentin and riluzole suggests that these compounds likely modulate both sensory and affective dimensions of pain.