Peripheral nerve injury induced chronic pain (PNICP) belongs to the categories of stubborn pains that constitute a major public health concern. Indeed, this category of pain, refractory to the currently available analgesics, causes persistent suffering in several thousands of patients with socio-economic problems such as substantial costs due to disability and decreased productivity (Fornasari, 2017, Romanelli et al., 2017, Ruff and Ruff, 2010, Soliman et al., 2023). Therefore, development of novel therapeutic strategies against stubborn pain is a great challenge for biomedical research. PNICP is a neuropathic pain generated by the lesions, injuries or constriction of peripheral nerves and the subsequent disturbances of the functions of the spinal cord (SC) and supraspinal neural networks that control nociception or pain transmission (Chalaki et al., 2022, Millan, 1999, Millan, 2002, Raja et al., 2020). Hence, it seems logical that drugs to be characterized/developed for an effective treatment of PNICP or neuropathic pain must necessarily be capable of modulating the activity of spinal and supraspinal neuronal pathways.

Because of their pleiotropic potential and diverse effects on the central (CNS) and peripheral (PNS) nervous systems, steroids have early been suspected to modulate pain sensation. Indeed, since 1927, Cashin and Moravek observed that intravenous injections of cholesterol were able to suppress pain sensation by exerting anesthetic effects in mammals (Cashin and Moravek, 1927). Afterwards, Selye demonstrated that certain pregnane steroids such as progesterone and deoxycorticosterone induce sedation and anesthesia in rat (Selye and Masson, 1942). Together, these observations paved the way for the development of various synthetic analogs of pregnane steroids that reduced pain through allosteric activation of GABAA receptors (Belelli and Lambert, 2005, Holzbauer, 1976, Huang et al., 2016, Kraulis et al., 1975, Majewska, 1992, Purdy et al., 1991). Since safe and effective therapeutic alternatives are rare, glucocorticosteroids and their analogs are used to alleviate inflammatory pain although they induce various side effects (for reviews, (Barnes, 1998, Belvisi and Hele, 2003). Glucocorticosteroids reduce inflammatory pain by inducing anti-inflammatory actions on the damaged nerve tissue that triggers nociceptive mechanisms leading to pain sensation. Anti-inflammatory effects of glucocorticosteroids result from their ability to inhibit the expression of collagenase (the key enzyme involved in tissue degeneration during inflammatory mechanisms) and pro-inflammatory cytokines or to stimulate the synthesis of lipocortin that blocks the production of eicosanoids (Barnes and Adcock, 1993, Fakih et al., 2002, Firestein et al., 1991, Sibilia, 2003). There is also clinical evidence supporting the use of glucocorticoids in the treatment of chronic neuropathic pain (Devor et al., 1985, Kingery, 1997, Lussier et al., 2004, Wareham, 2004). Experimental investigations in animals suggest that glucocorticoids may inhibit the initiation of neuropathic pain states or attenuate this pain but the mechanisms of action are unknown (Clatworthy et al., 1995, Devor et al., 1985, Johansson and Bennett, 1997, Kingery et al., 1999, Takeda et al., 2004). Anti-inflammatory actions of glucocorticosteroids are supposed to contribute to the inhibition of neuroinflammatory component of neuropathic pain but there is no specific evidence supporting this idea. As an interesting finding revealed that the endoneurial expression of pro-inflammatory cytokines may have a role in the genesis of neuropathic pain, glucocorticosteroids may reduce this pain through the modulation of neuroimmune interactions (Sommer and Kress, 2004). In support of this hypothesis, it has been shown that the glucocorticoid triamcinolone, which reduced the neuropathic pain seen in the model of post-traumatic peripheral neuropathy, also decreased the number of endoneurial mast cells expressing (in the injured nerve) the pro-inflammatory cytokine tumor necrosis factor-alpha (Hayashi et al., 2008). Altogether, the findings reviewed above strongly support the existence of key actions of endogenous and synthetic steroids in the modulation of inflammatory, PNICP or neuropathic pain.

As the nervous system is the target of various hormonal compounds including steroids, several investigations strive to decipher the interactions between steroids and nerve cells that may pivotally determine or modulate chronic pain transmission. While a majority of studies focus on the brain, the SC received little attention although this structure is also an important part of the CNS controlling motor and sensory functions. To point out the importance of interactions between steroidal hormones and the SC, here we review several key data revealing that the SC plays a pivotal role in nociception, PNICP or neuropathic pain modulation, crucially depending on its ability to synthesize endogenous steroids or neurosteroids via the process of neurosteroidogenesis (for reviews, Baulieu et al., 1999, Mensah-Nyagan et al., 1999).