Long-Lasting Nociplastic Pain Modulation by Repeated Administration of Sigma-1 Receptor Antagonist BD1063 in Fibromyalgia-like Mouse Models

Abstract

Sigma-1 receptor (s1R) ligands have been shown to be effective at relieving neuropathic and inflammatory pain, but have not yet been tested in experimental models of fibromyalgia. The objective of this study was to evaluate the effect of a s1R antagonist (BD1063) compared to pregabalin. ICR-CD1 female mice were subjected to either six repeated injections of reserpine, to cause reserpine-induced myalgia (RIM6), or acidified saline intramuscular injections (ASI). In these two models, we evaluated the effect of BD1063 and pregabalin on thermal hypersensitivity, anxiety-like and depression-like behaviors, and on spinal cord gliosis. BD1063 exerted an antinociceptive effect on both reflexive (thermal hyperalgesia) and nonreflexive (anxiety- and depression-like) pain behaviors, and reduced spinal astroglial and microglial reactivity, following repeated treatment for 2 weeks. Interestingly, the effects of BD1063 were long-term, lasting several weeks after treatment discontinuation in both fibromyalgia-like models. Similar results were obtained with pregabalin, but the effects on pain behaviors lasted for a shorter length of time, and pregabalin did not significantly modulate spinal glial reactivity. The inhibitory and long-lasting effect of pharmacological blockade of s1Rs on both sensory and affective dimensions of nociplastic-like pain and spinal cord gliosis in two experimental models of fibromyalgia support the application of this therapeutic strategy to treat fibromyalgia.

Natural polyphenolic coffee extract administration relieves chronic nociplastic pain in a reserpine‐induced fibromyalgia‐like female mouse model

“…On the other hand, spinal cord gliosis has been suggested to play a crucial role in nociplastic pain responses development, as shown in the RIM6 mice (Álvarez-Pérez, Bagó-Mas, et al, 2022;. To gain mechanistic insights, the modula- other inflammatory disorders (Atanasov et al, 2021;Schmidt et al, 2007), it is not unreasonable to hypothesize that the combination several natural polyphenolic extracts may be also a not available yet potential therapeutic strategy for patients suffering nociplastic pain conditions.…”

“…The reserpine‐induced myalgia RIM6‐mice mouse model of FM‐like condition was used in this study (Álvarez‐Pérez, Bagó‐Mas, et al., 2022 ). Reserpine (Sigma‐Aldrich) dissolved in acetic acid and diluted to a final concentration of 0.5% acetic acid with saline solution was administered subcutaneously (0.25 mg/kg) on days 0, 1, 2, 9, 16, and 23.…”

“…and the spinal cord segment distal to T10 was collected to determine both microgliosis and astrogliosis. The immunohistochemical analyses were performed fol-lowing the processes previously described (Álvarez-Pérez, Bagó-Mas, et al, 2022;Bagó-Mas et al, 2022;Soler-Martínez et al, 2022). National Institutes of Health).…”

“…In light of these findings, the present work aimed to determine whether the decaffeinated CE may exert antinociceptive effects in a FM‐like female model (RIM6 model) that develops chronic nociplastic pain and central nervous system gliosis (Álvarez‐Pérez, Bagó‐Mas, et al., 2022 ; Álvarez‐Pérez, Deulofeu, et al., 2022 ). To this end, RIM6 adult ICR‐CD1 female mice received 1‐week repeated administration of either 10 or 15 mg/kg of coffee extract, and reflexive and nonreflexive pain responses were assessed within 3 weeks of the experimental period.…”

Microbiological and Physiological Effects of Pain

“…Utilizing the mechanism of nociplastic pain, a fibromyalgia-like mouse model was able to demonstrate that antagonization of the sigma-1 receptor resulted in alleviation long-term nociplastic pain, implicating its potential role in the mechanism [ 63 ]. In an analysis of 605 patients with or without chronic nociplastic pain conditions that commonly overlap (painful temporomandibular disorder, irritable bowel syndrome, fibromyalgia, low back pain, headache), a possible important difference was discovered in the polyunsaturated fatty acid (PUFA) levels [ 64 ].…”