Long-lasting reflexive and nonreflexive pain responses in two mouse models of fibromyalgia-like condition

Abstract

Nociplastic pain arises from altered nociception despite no clear evidence of tissue or somatosensory system damage, and fibromyalgia syndrome can be highlighted as a prototype of this chronic pain subtype. Currently, there is a lack of effective treatments to alleviate both reflexive and nonreflexive pain responses associated with fibromyalgia condition, and suitable preclinical models are needed to assess new pharmacological strategies. In this context, although in recent years some remarkable animal models have been developed to mimic the main characteristics of human fibromyalgia, most of them show pain responses in the short term. Considering the chronicity of this condition, the present work aimed to develop two mouse models showing long-lasting reflexive and nonreflexive pain responses after several reserpine (RIM) or intramuscular acid saline solution (ASI) injections. To our knowledge, this is the first study showing that RIM6 and ASI mouse models show reflexive and nonreflexive responses up to 5–6 weeks, accompanied by either astro- or microgliosis in the spinal cord as pivotal physiopathology processes related to such condition development. In addition, acute treatment with pregabalin resulted in reflexive pain response alleviation in both the RIM6 and ASI models. Consequently, both may be considered suitable experimental models of fibromyalgia-like condition, especially RIM6.

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

“…Previous studies have shown that σ1R antagonists are able to modulate pathological pain in several preclinical models [ 21 ], but their potential modulatory effects on nociplastic pain remain to be investigated. To this end, an acute dose–response (15, 20, 25, 40, or 60 mg/kg) method was designed to determine whether the σ1R antagonist BD1063 exerts antinociceptive effects in two fibromyalgia-like models with long-lasting nociplastic pain: reserpine-induced myalgia RIM6 mice [ 7 , 28 ] and intramuscular acid saline solution injection ASI mice [ 7 , 29 ]. Withdrawal latency to thermal stimulation was assessed immediately before (preadministration) and 30 min after (postadministration) compound treatment.…”

“…The effect of BD1063 administered twice a day (i.p. ; 6 h between administrations) at 40 mg/kg during 2 weeks after fibromyalgia-like induction was compared with the effect of pregabalin, an FDA-approved drug for fibromyalgia syndrome treatment [ 35 , 36 ], administered once a day at 20 mg/kg, a dose that exerts maximum antinociceptive effects in either RIM6 or ASI models, according to a recent dose–response study in our laboratory [ 7 ]. Thermal hyperalgesia was evaluated weekly on a long-term basis, extending to several weeks after the discontinuation of the 2-week treatment.…”

“…One hurdle in drawing meaningful and reliable translational conclusions from animal experiments is the limitation in our ability to model complex diseases with unclear etiology, such as fibromyalgia. Two main models of fibromyalgia-like conditions have been described to mimic altered, long-lasting, reflexive and nonreflexive pain-related behaviors [ 7 ]. In an experimental model of reserpine-induced myalgia (RIM3) with three injections of reserpine, the effect of various drugs has been tested in mice, including TRPV1 receptor antagonists [ 8 ], serotonin transporters inhibitors [ 9 ], bradykinin receptor antagonists [ 10 ], ligands of the nociceptin/orphanin FQ receptor [ 11 ], dopaminergic receptor agonists [ 12 ], toxins [ 13 , 14 , 15 ], gabapentinoids [ 14 ], resolvins [ 16 ], and plant-based polyphenol products [ 17 , 18 , 19 ].…”

“…In an experimental model of reserpine-induced myalgia (RIM3) with three injections of reserpine, the effect of various drugs has been tested in mice, including TRPV1 receptor antagonists [ 8 ], serotonin transporters inhibitors [ 9 ], bradykinin receptor antagonists [ 10 ], ligands of the nociceptin/orphanin FQ receptor [ 11 ], dopaminergic receptor agonists [ 12 ], toxins [ 13 , 14 , 15 ], gabapentinoids [ 14 ], resolvins [ 16 ], and plant-based polyphenol products [ 17 , 18 , 19 ]. In mice subjected to intramuscular injection of acidified saline solution (ASI), the effect of gabapentinoids [ 7 ] and plant-based polyphenol products [ 20 ] has also been tested. These studies mainly involved short-term assessment of reflexive responses (i.e., thermal hyperalgesia or mechanical allodynia).…”

“…These studies mainly involved short-term assessment of reflexive responses (i.e., thermal hyperalgesia or mechanical allodynia). However, little is known about the long-term pharmacological effects derived from a more suitable model, such as the RIM6 mouse model, which has been recently described to exhibit long-lasting reflexive and nonreflexive pain abnormalities similar to those in the chronic condition of fibromyalgia [ 7 ]. Among possible new pharmacological strategies to alleviate long-term nociplastic pain, we focused on the sigma-1 receptor (σ1R), since there is a growing body of preclinical evidence demonstrating the efficacy of σ1R antagonists in relieving pain in various models of neuropathic and inflammatory pain [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”