5α-reduced neuroactive steroids alleviate thermal and mechanical hyperalgesia in rats with neuropathic pain

5α-reduced neuroactive steroids with selective modulatory action in vitro on T or combined modulatory action on T and GABA_A currents present in peripheral sensory neurons have been shown to induce potent peripheral analgesia in vivo in intact animals. Although the role of T and GABA_A currents in pathophysiology of neuropathic pain (NPP) is not established, it appears that blockade of T currents and/or potentiation of GABA_A currents could be beneficial in the management of NPP. To study the potential usefulness of 5α-reduced neuroactive steroids in alleviating NPP, we selected two newly synthesized steroids - ECN and CDNC24 - with a selective blocking effect on T currents and a selective potentiating effect on GABA_A currents, respectively, and commercial analogs - alphaxalone and 3α5αP - with the effects on both ion channels. We used a sciatic nerve ligation model to induce thermal and mechanical hyperalgesia in adult rats and tested peripheral thermal and mechanical nociception following local injection of neuroactive steroids into the peripheral receptive fields of a ligated hind paw. We found that 5α-reduced neuroactive steroids alleviate thermal and mechanical hyperalgesia in NPP rats. ECN and CDNC24 were more selective in alleviating thermal nociception in NPP than in sham animals when compared to 3α5αP and alphaxalone although the anti-nociceptive effect induced by 3α5αP and alphaxalone was more profound. CDNC24 was most selective since it had very minimal anti-nociceptive effect in sham animals but a very profound anti-nociceptive effect in NPP animals suggesting that, under pathological conditions, peripheral GABA_A receptors might be an attractive therapeutic target.