Neurosteroids in Pain Management: A New Perspective on an Old Player

Abstract

Since the discovery of the nervous system’s ability to produce steroid hormones, numerous studies have demonstrated their importance in modulating neuronal excitability. These central effects are mostly mediated through different ligand-gated receptor systems such as GABAA and NMDA, as well as voltage-dependent Ca2+ or K+ channels. Because these targets are also implicated in transmission of sensory information, it is not surprising that numerous studies have shown the analgesic properties of neurosteroids in various pain models. Physiological (nociceptive) pain has protective value for an organism by promoting survival in life-threatening conditions. However, more prolonged pain that results from dysfunction of nerves (neuropathic pain), and persists even after tissue injury has resolved, is one of the main reasons that patients seek medical attention. This review will focus mostly on the analgesic perspective of neurosteroids and their synthetic 5α and 5β analogs in nociceptive and neuropathic pain conditions.

The T-type calcium channel isoform Cav3.1 is a target for the hypnotic effect of the anaesthetic neurosteroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile

“…Neurosteroids have sedative/hypnotic properties, with the introduction of alphaxalone and its related 3a,5a analogues 15 in the 1970s, which were withdrawn from clinical use because of a relatively high incidence of anaphylactic reactions to the vehicle. 16,17 However, alphaxalone has been reformulated recently and is used in veterinary medicine.…”

Serum levels of allopregnanolone, progesterone and testosterone in menstrually-related and postmenopausal migraine: A cross-sectional study

“…In preclinical experimental models, allopregnanolone exhibits pronounced analgesic properties, but few studies focused on the relationship between pain and allopregnanolone in clinical populations ( 32 ). Two studies in US Army male veterans show that allopregnanolone levels are inversely related to pain (muscle soreness, chest pain, low back pain and total pain, including headache), suggesting that allopregnanolone may act as a potent endogenous analgesic and that supplementation with exogenous allopregnanolone could have therapeutic potential ( 33 , 34 ).…”

Inhibition of Cytochrome P450 Side-Chain Cleavage Attenuates the Development of Mechanical Allodynia by Reducing Spinal D-Serine Production in a Murine Model of Neuropathic Pain

“…Neurosteroids are locally synthesized in the central nervous system and are involved in modulating a number of neural functions including nociception (Yoon et al, 2010; Joksimovic et al, 2018). It has been suggested that direct administration of neurosteroids regulates many pathophysiological responses, but use of neurosteroids to treat epilepsy, neuropsychiatric disorders, pain, and other neurologic issues has been met with several challenges, including pharmacokinetics, low bioavailability, safety, and tolerability, which limit its therapeutic use.…”

“…Then, PREG can be converted to dehydroepiandrosterone (DHEA) by cytochrome P450c17 or to progesterone by 3β-hydroxysteroid dehydrogenase (Compagnone and Mellon, 2000). It has been suggested that neurosteroids are related to the modulation of nociception; thus, neurosteroidogenic enzymes can be potential key therapeutic targets for pain control (Yoon et al, 2010; Porcu et al, 2016; Joksimovic et al, 2018). In previous studies from our laboratories, we suggested that the expression of cytochrome P450c17 is significantly increased in spinal astrocytes following chronic constriction injury (CCI) of the sciatic nerve and inhibition of this enzyme reduces not only the pathophysiological activation of spinal astrocytes but also the development of neuropathic pain (Choi et al, 2019a; Choi et al, 2019c).…”