Prolonged Gabapentin Analgesia in an Experimental Mouse Model of Fibromyalgia

Abstract

In a new mouse model for generalized pain syndrome, including fibromyalgia, which used intermittent cold stress (ICS), bilateral allodynia in the hindpaw was observed that lasted more than 12 days; thermal hyperalgesia lasted 15 days. During constant cold stress (CCS), mice showed only a transient allodynia. A female prevalence in ICS-induced allodynia was observed in gonadectomized but not in gonad intact mice. Systemic gabapentin showed complete anti-allodynic effects in the ICS model at the one-tenth dose for injury-induced neuropathic pain model, and central gabapentin showed long-lasting analgesia for 4 days in ICS, but not the injury model. These results suggest that the ICS model is useful for the study of generalized pain syndrome. FindingsFibromyalgia syndrome (FMS) is a highly prevalent (~2% of all citizens) chronic pain disease, which has unique characteristics including generalized or widespread allodynia and a female preponderance [1][2][3][4]. According to recent reports, physical and psychological stressors are believed to trigger FMS [5][6][7][8][9]. Although there are several trials underway to make existing medicines available for FMS treatment, attempts to develop a compound specific for FMS are yet to be performed. One reason is the lack of established experimental animal models for FMS, although several models have been proposed [10][11][12][13]. Here, we report a pharmacological study using a new generalized chronic pain or FMS model, using intermittent cold stress.We improved the mouse model for dysautonomia, also referred to as the specific alternation of rhythm in temperature (SART) model [14,15]. To develop the stress model of mice with reproducible and long-lasting allodynia and hyperalgesia, we evaluated several different stress paradigms. With regard to a temperature of the cold room, the temperature of 4 ± 2°C gave rise to long-lasting allodynia. At the temperature over 6°C, long-lasting and stable allodynia was not observed. For quick changes in temperature between 4 and 24°C, we used a meshed stainless steel floor in each cage, and transferred mice individually, leaving the stainless floor in the cold room. Trials with different numbers of mice in the same cage, ranging from one to eight mice, revealed that the number of mice in the same cage should be two. Although frequent temperature change is expected to be more stressful, an interval of more than 30 min was estimated to be minimal for the switch between 4 and 24°C. To maintain healthy conditions in the cold room, food pellets and gelatin as the water supply were placed on the floor of the cage in the cold room, owing to the lowered spontaneous activities of mice in such conditions. For stable nociception, an adaptation period of at least 1 h before the nociception tests was necessary.

Gabapentin Attenuates the Activation of Transient Receptor Potential A1 by Cinnamaldehyde

“…(Garry et al, 2005;Cheng and Chiou, 2006;Arnold et al, 2007;Dworkin et al, 2007;Gilron et al, 2007;Nishiyori et al, 2008). The mechanism of the analgesic action of gabapentin is still not clear but the recent reports proposed that gabapentin might act on several receptors and ion channels expressed in the dorsal root ganglia (DRG) or in the spinal cord dorsal horn neurons (Luo et al, 2001).…”

Animal Models of Fibromyalgia

“…In mice, the effective dose for relieving hyperalgesia in the repeated cold stress model was over three times smaller than that for reducing nerve injury-induced neuropathic pain, despite the effective dose of pregabalin being similar between fibromyalgia and neuropathic pain patients in a clinical setting (Dworkin et al, 2007;. Further, intracerebroventricular administration of gabapentin significantly attenuated hyperalgesia in the repeated cold stress model but not in the neuropathic pain model, possibly because up-regulation of the α2δ1 subunit may underlie the mechanism for repeated cold stress-induced hyperalgesia (Nishiyori and Ueda, 2008). No clear evidence has yet been presented that opiate drugs are effective in reducing pain in fibromyalgia patients, as no randomized controlled double blind clinical trial on opiates has been conducted with a sufficient number of fibromyalgia patients (Clauw, 2009).…”

“…A nociception test is then conducted at room temperature at least 1 h after the end of stress exposure. Nishiyori and Ueda (2008) found that mice exhibited thermal hyperalgesia (reduction in paw withdrawal latency in response to thermal stimulation) and mechanical hyperalgesia (reduction in threshold for paw withdrawal in response to mechanical stimulation by the von Frey apparatus) for more than 12 days following the repeated cold stress. In contrast, mice exposed to constant cold temperature (4C) stress manifest only short-lasting hyperalgesia.…”

“…The repeated cold stress test performed by Nishiyori and Ueda (2008) caused long-lasting (12 days or more) mechanical and thermal hyperalgesia in the paws of both male and female mice, suggesting no apparent difference in susceptibility to repeated cold stress between genders. Intriguingly, gonadectomized male mice showed partial reversal of the repeated cold stress-induced mechanical hyperalgesia, whereas gonadectomized females did not.…”

“…This procedure was repeated for 5 days or more (Kita et al, 1975;Hata et al, 1995). Nishiyori and Ueda (2008) revisited this stress model to demonstrate its utility as a putative animal model for fibromyalgia. They optimized the repeated cold stress protocol to induce long lasting mechanical and thermal hyperalge s i a i n m i c e a s f o l l o w s .…”