**Background:** Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain, fatigue, sleep disturbance, cognitive impairment, and mood disorder. It is classified as nociplastic pain, distinct from nociceptive and neuropathic pain. Only three FDA-approved drugs exist for FM (pregabalin, duloxetine, milnacipran), and they have limited efficacy and side effects. NSAIDs and opioids are ineffective in FM patients. To develop better treatments, animal models that mimic FM pathophysiology and pharmacotherapy are needed. This review focuses on two mouse models developed by the authors: intermittent cold stress-induced generalized pain (ICGP) and intermittent psychological stress-induced generalized pain (IPGP).
**Methods:** For the ICGP model, C57BL/6J mice (18–22 g) were housed in pairs and exposed to intermittent cold stress: they were placed in a cold room at 4 ± 2°C overnight, then subjected to alternating 30-minute periods at 24°C and 4°C during the day, repeated for two days. On day 3 (post-stress day 1, P1), mice were removed and tested after at least 1 hour adaptation. For the IPGP model, mice were placed in a communication box with nine compartments. Five mice received foot shocks (0.6 mA, 1 s, 120 times) while four mice in adjacent compartments (with insulated floors) were exposed to psychological stress (seeing, hearing, smelling the shocked mice). Stress was given once daily for 5 days. Nociception was assessed using mechanical paw pressure (von Frey), thermal paw withdrawal (Hargreaves), muscle pressure (Randall-Selitto), and electrical stimulation (Neurometer). Plasma corticosterone was measured. Pharmacological treatments included morphine, diclofenac, pregabalin, duloxetine, mirtazapine, donepezil, and LPAR1 antagonists. Knockout mice (LPAR1, NR2A) and siRNA were used to study mechanisms.
**Key Results:** Both ICGP and IPGP models produced long-lasting hyperalgesia lasting at least P13–P19. In ICGP, mechanical hyperalgesia was observed in both hind paws and femoral muscle; thermal hyperalgesia lasted until at least P17. Electrical stimulation showed allodynia specific to Aδ (250 Hz) and Aβ (2000 Hz) fibers, but not C fibers. In IPGP, hyperalgesia was observed in mechanical, thermal, and muscle pain tests, but not in visceral pain (capsaicin colon test). Plasma corticosterone increased transiently (peak at P2 in ICGP; ~3.5-fold in IFS and ~2.2-fold in IPS). Sex differences: no significant difference in intact mice, but after gonadectomy, male mice showed reduced hyperalgesia (ICGP and IPGP), while females remained hyperalgesic. LPAR1 knockout mice showed complete loss of hyperalgesia in both models. Pharmacotherapy: Diclofenac (10 mg/kg i.p.) and morphine (i.c.v. or s.c.) were ineffective in both models. Pregabalin (1 mg/kg i.p. or 1 μg i.c.v.) showed potent anti-hyperalgesia, with brain-specific effects (i.c.v. more effective than i.t.). Duloxetine (30 mg/kg i.p. or 1 μg i.t.) was effective. Mirtazapine (1 mg/kg i.p. or 1 μg i.c.v.) reversed hyperalgesia, and repeated treatment (every other day from P5 to P13) completely normalized pain threshold until at least P17. Donepezil (10 μg/kg i.p. or 10 μg i.c.v.) also reversed hyperalgesia, and repeated daily treatment from P5 to P10 normalized threshold until P18. LPAR1 antagonist AM966 (1 nmol i.c.v. repeated from P5 to P11) abolished established hyperalgesia. The loss of central morphine analgesia in ICGP was reversed by NR2A knockout or siRNA into the periaqueductal gray (PAG). Mirtazapine restored morphine analgesia after repeated treatment.
**Clinical Implications:** The ICGP and IPGP models closely mimic clinical FM features: long-lasting widespread pain, female predominance after gonadectomy, lack of response to NSAIDs and opioids, and efficacy of pregabalin and duloxetine. The models also reveal potential radical treatments: repeated mirtazapine, donepezil, or LPAR1 antagonists can erase pain memory, suggesting they may target underlying mechanisms rather than just symptoms. However, limitations include the relatively short duration of hyperalgesia (weeks vs. ≥3 months in clinical FM) and the need for more mechanistic studies on brain circuits and immunity. These models are valuable for preclinical testing of new FM therapies, but clinical validation is required.