Background & Aims
“Nociplastic pain” is defined as pain that arises from altered nociception without nociceptor activation and nerve injury (Kosek et al., 2021).
Diseases with nociplastic pain include fibromyalgia, irritable bowel syndrome, and burning mouth syndrome. We have developed and reported two types of nociplastic pain murine models: 1) the inflammation-induced widespread pain (iWS) model and 2) the amygdala activation-dependent widespread pain (aWS) model (Sugimoto et al., 2021). We have already demonstrated that the iWS involves activation of the bilateral parabrachial nucleus and the right central amygdala, indicating the sensitization is resulted from the activation of amygdala pain system. The aim of this study was to compare the effects of conventional analgesics with different mechanisms on nociplastic sensitization in the hindlimbs in these models.
Methods
The iWS model was produced by injecting formalin subcutaneously into the whisker pad of mice. The aWS model was produced by injecting deschloroclozapine (DCZ; 0.1 mg/kg, i.p.) into mice expressing hM3Dq receptors in neurons in the right central amygdala. In these models demonstrating widespread sensitization, we compared the effects of gabapentinoids (pregabalin (PGB) and mirogabalin (MGB)), a non-steroidal anti-inflammatory drug (celecoxib, CLX), and acetaminophen (AcAph, a centrally acting analgesic). We evaluated bilateral 50%-paw withdrawal thresholds (PWT50) using von Frey filaments with up-down methods. We also video-captured the movement of the mice and analyzed the movement pattern.
Results
In both models, PWT50 significantly decreased for >10 days after a single facial injection of formalin (iWS model) and for around 2 hours after systemic injection of 0.1 mg/kg of DCZ (aWS model). In the iWS model, MGB (10 mg/kg) and PGB (30 mg/kg) significantly elevated the PWT50 to a level not significantly different from the pre-formalin value (two-way ANOVA followed by post-hoc Dunnett test, n = 34). In contrast, the PWT50 was not significantly influenced by CLX (20 mg/kg, i.p.) in the iWS model, regardless of the timing of injection. In the aWS model, MGB (10 mg/kg) and PGB (30 mg/kg) significantly attenuated the effect of DCZ (two-way ANOVA followed by post-hoc Dunnett test and Gabriel test, n = 8).
Conclusions
The ?2?-1 molecules are densely expressed in the central and basolateral amygdala, parabrachial nucleus, and periaqueductal gray (PAG) (the Allen Brain Atlas mouse ISH), all involved in amygdala-mediated central pain regulation. It is likely that gabapentinoids exerted their effects by modulating these brain structures. AcAph is shown to affect nociceptive signaling in the rostroventromedial medulla, which is under control of the PAG, another main target of the amygdala system. Developing drugs affecting this amygdala system would be promising in the pharmacotherapy of nociplastic pain.
References
1) Kosek et al., Pain, 2021
2) Sugimoto et al., Pain, 2021
3) the Allen Brain Atlas mouse ISH
Presenting Author
Manami Yajima
Poster Authors
Manami Yajima
OTHR
Tsurumi University School of Dental Medicine
Lead Author
Fusao Kato Ph.D
Center for Neuroscience of Pain, The Jikei University School of Medicine, Tokyo, Japan
Lead Author
Yukari Takahashi Ph.D
Center for Neuroscience of Pain, The Jikei University School of Medicine, Tokyo, Japan
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Nociplastic and chronic widespread pain