Analgesic strategies aimed at stimulating the endogenous production of allopregnanolone

Abstract

A growing number of studies indicate that 3-alpha reduced neurosteroids are remarkable analgesics in various pain states. This is the case for allopregnanolone (AP), one of the most potent endogenous positive allosteric modulators of GABAA receptor function. From the pioneering work of Hans Selye, who described the sedative properties of steroids, synthetic compounds resembling the progesterone metabolite AP have been developed. If some of them have been used as anesthetics, it seems difficult to propose them as a therapeutic option for pain since they display several adverse side effects such as sedation, amnesia and functional tolerance. An alternative strategy, chosen by few laboratories around the world, is aimed at stimulating the local production of 3-alpha reduced neurosteroids in order to limit these well-known side effects. This pharmacological approach has the advantage of targeting specific structures, fully equipped with the necessary biosynthetic enzymatic machinery, where neurosteroids already act as endogenous pain modulators. The various pharmacological trials which attempted to treat pain symptoms by stimulating the production of 3-alpha reduced neurosteroids are reviewed here, as well as novel neurotransmitter systems possibly regulating their endogenous production.

Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations

“…Neurosteroids are steroidal hormones that are synthesized in the brain, and exert inhibitory effects mainly via GABA A receptors, glycine, and L-and T-type calcium channels [145][146][147][248][249][250][251]. Among the most common neurosteroids are progesterone, pregnanolone, and allopregnanolone.…”

“…Studies have revealed neurosteroids to have a therapeutic role in a number of conditions such as epilepsy, drug withdrawal-induced seizures, anxiety, premenstrual syndrome, stress, depression, and alcohol withdrawal. Furthermore, it is possible that some neurosteroids are produced in the nervous system in response to injury, exerting anti-inflammatory effects at the site of insult [145,251]. Of particular relevance to pain and opioid research is neurosteroids' role in modulating neuronal plasticity and related activities of the nervous system, as well as their role in the sexual dimorphism of pain processing [145].…”

“…Subsequent to the finding that neurosteroids produce anesthesia in rat models and thus suppress pain sensation [252][253][254], neurosteroids have been found to promote analgesia [251,255], and have documented efficacy in the treatment of neuropathic pain [145]. Whereas lower levels of testosterone or progesterone have been associated with low nociceptive thresholds, injecting these steroidal hormones has been found to elicit analgesia [251,[256][257][258][259][260].…”

“…Whereas lower levels of testosterone or progesterone have been associated with low nociceptive thresholds, injecting these steroidal hormones has been found to elicit analgesia [251,[256][257][258][259][260]. Several studies have also found that higher levels of progesterone decrease anesthetic [261] and postoperative analgesic requirements [262].…”

Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone

“…However, there is a much faster pathway that alters ion channel activity through steroid activation of membrane receptors. Nongenomic signaling of the steroid hormone progesterone (P4) occurs on a time scale of seconds and is required for distinct physiological events, such as oocyte maturation (3) and human sperm cell activation (4, 5), and P4 likely triggers anesthesia in rodents (6). Many tissues have both nuclear and membrane progesterone receptors, which complicates identification of the latter.…”