Salvia rosmarinus Antinociceptive Efficacy Depends on Sex and Involves Hormonal Mechanisms in Experimental Fibromyalgia-Like Pain

Fibromyalgia (FM) is a chronic, widespread musculoskeletal pain syndrome of still unknown etiology, characterized by allodynia and hyperalgesia. It affects between 2% and 8% of the population and is significantly more prevalent in women than in men. It is attributed to physiological, endocrine, immunological, and neurobiological variations that influence both pain development and the response to pharmacological treatments. Limited efficacy and a high incidence of adverse effects of current pharmacological treatments for FM have increased interest in the use of alternative therapies with medicinal plants. Non-polar extracts such as the essential oil of Salvia rosmarinus are included in herbal formulations, suggesting their potential properties against nociplastic pain. However, the evidence regarding the efficacy and mechanisms of action according to sex remains unexplored. The objective in this study was to investigate the efficacy of a non-polar extract of S. rosmarinus, whose GC-MS profile is described, and to explore the involvement of gonadal hormone receptors in an experimental model of FM-like pain in male and female rats. A hexane extract of the aerial parts of S. rosmarinus (10, 30 and 300 mg/kg, i.p.) or gabapentin (30 mg/kg, i.p., as a reference drug) was evaluated 30 min after its administration by using the Von Frey filaments and thermal acetone test for tactile and mechanical allodynia, respectively, and the Randall Sellito test for mechanical hyperalgesia was carried out for a period of 240 min. To determine the involvement of gonadal hormone receptors, reserpinized female rats were pretreated with the selective estrogen receptor β antagonist (ERβ, PHTPP, 25 µg/rat) 24 h before the extract, while male rats received non-steroidal antiandrogen pretreatment with flutamide (10 mg/kg/day) for 14 days, followed by behavioral testing. The extract produced a dose-dependent antiallodynic and antihyperalgesic effects, with greater efficacy in females compared to males, as the effects were significant starting at a dose of 30 mg/kg, while in males only the highest dose was significant. Blockade of ERβ receptors inhibited the extract effects in females, while androgen blockade facilitated the effects in males. The results of this study suggest that non-polar metabolites are involved in the antiallodynic and antihyperalgesic efficacy of S. rosmarinus mediated by sex-dependent gonadal hormonal mechanisms for FM-type pain relief.