5alpha-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 5alpha-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 3alpha5alphaP-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 5alpha-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 3alpha5alphaP and
alphaxalone although the anti-nociceptive effect induced by 3alpha5alphaP 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.