Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain

Abstract

Because the treatment and management of neuropathic pain are extremely complicated, the characterization of novel analgesics and neuroprotectors with safe toxicological profiles is a crucial need to develop efficient therapies. Several investigations revealed that the natural neurosteroid allopregnanolone (AP) exerts analgesic, neuroprotective, antidepressant and anxiolytic effects. These effects result from AP ability to modulate GABA(A), glycine, L- and T-type calcium channels. It has been shown that AP treatment induced beneficial actions in humans and animal models with no toxic side effects. In particular, a multi-parametric analysis revealed that AP efficiently counteracted chemotherapy-evoked neuropathic pain in rats. It has also been demonstrated that the modulation of AP-producing enzyme, 3α-hydroxysteroid oxido-reductase (3α-HSOR), in the spinal cord regulates thermal and mechanical pain thresholds of peripheral nerve injured neuropathic rats. The painful symptoms were exacerbated by intrathecal injections of provera (pharmacological inhibitor of 3α-HSOR) which decreased AP production in the spinal cord. By contrast, the enhancement of AP concentration in the intrathecal space induced analgesia and suppression of neuropathic symptoms. Moreover, in vivo siRNA-knockdown of 3α-HSOR expression in healthy rat dorsal root ganglia increased thermal and mechanical pain perceptions while AP evoked a potent antinociceptive action. In humans, blood levels of AP were inversely associated with low back and chest pain. Furthermore, oral administration of AP analogs induced antinociception. Altogether, these data indicate that AP, which possesses a high therapeutic potential and a good toxicological profile, may be used to develop effective and safe strategies against chronic neuropathic pain.

Keywords: 17β-HSD; 17β-hydroxysteroid dehydrogenase; 21-OHase; 21-hydroxylase; 2′,3′-cyclic nucleotide 3′-phosphodiesterase; 3α,5α-tetrahydroprogesterone or allopregnanolone; 3α-HSOR; 3α-hydroxysteroid oxido-reductase; 3β-HSD; 3β-hydroxysteroid dehydrogenase; 5α-R; 5α-reductase; AP; CNPase; CV; DH; DHDOC; DHEA; DHEAS; DHP; DHT; DOC; GABA; HST; IENF; NAP; Neuropathic pain; Neuroprotection; Neurosteroid; Nociception; OXAL; P450c17; P450scc; PREG; PREGS; PROG; SC; THDOC; Therapeutic strategies; VINC; conduction velocity; cytochrome P450c17 or 17α-hydroxylase/17,20 lyase; cytochrome P450side-chain cleavage; dehydroepiandrosterone; dehydroepiandrosterone sulfate; deoxycorticosterone; dihydrodeoxycorticosterone; dihydroprogesterone; dihydrotestosterone; dorsal horn; gamma-aminobutyric acid; hydroxysulfotransferase; intraepidermal nerve fibers; nerve action potential; oxaliplatin; pregnenolone; pregnenolone sulfate; progesterone; spinal cord; tetrahydrodeoxycorticosterone; vincristine.