Role of glutamate receptors in the dorsal reticular nucleus in formalin‐induced secondary allodynia

Abstract

The role of glutamate receptors present in the medullary dorsal reticular nucleus (DRt) in the formalin test and formalin-induced secondary nociception was studied in rats. Secondary mechanical allodynia was assessed with von Frey filaments applied to the rat's hindpaw, and secondary thermal hyperalgesia was evaluated with the tail-immersion test. The selective glutamate receptor antagonists MK801 (N-methyl-D-aspartate receptor antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (AMPA/KA receptor antagonist) and A841720 (metabotropic glutamate 1 receptor antagonist) were injected into the DRt before or 6 days after formalin injection in the rat. In the formalin test, the three antagonists significantly reduced the number of flinches in both phases of the test. DRt microinjection of MK801 or A841720, but not of CNQX, reduced both secondary nociceptive behaviors. Moreover, pre-treatment with the three antagonists injected into the DRt prevented the development of secondary mechanical allodynia and secondary thermal hyperalgesia. Similarly, in these rats, the number of c-Fos-like immunoreactive neurons were markedly reduced in both the superficial and deep lamina of the dorsal horn. Our findings support the role of DRt as a pain facilitator in acute and chronic pain states, and suggest a key role of glutamate receptors during the development and maintenance of formalin-induced secondary allodynia.

Systemic TAK-242 prevents intrathecal LPS evoked hyperalgesia in male, but not female mice and prevents delayed allodynia following intraplantar formalin in both male and female mice: The role of TLR4 in the evolution of a persistent pain state

“…ipsilateral versus contralateral limb). However, we found that, consistent with previous reports (Fu et al, 2000; Ambriz-Tututi et al, 2013), all mice showed bilateral effects (e.g. allodynia in both the ipsilateral and contralateral limbs in vehicle-treated mice) (data not shown), and we then averaged data from the two hindlimbs for analysis.…”

“…Previous work has shown that animals will exhibit behavior indicative of tactile allodynia when tested seven-days after formalin administration (Ambriz-Tututi et al, 2013; Fu et al, 2000; Fu et al, 2001). To begin, we examined baselines across groups and found no differences in tactile reactivity on day 0 ( p > 0.05).…”

“…The intraplantar injection of formalin leads to an initial period of high frequency afferent traffic with attendant flinching of the injected paw. After an interval of several days, a prominent tactile allodynia is observed (Ambriz-Tututi et al, 2013; Fu et al, 1999; Fu et al, 2000; Vierck et al, 2008; Wu et al, 2004; Zhang et al, 2007; Ambriz-Tututi et al, 2009). We believe that these preclinical observations parallel human conditions wherein acute tissue inflammation or injury may transition to a chronic pain state.…”

Reticular Formation and Pain: The Past and the Future

“…The DRt facilitates acute and short-lasting inflammatory pain (Almeida et al, 1996, 1999; Ambriz-Tututi et al, 2013; Martins et al, 2013, 2015a). Stimulation of the DRt by local administration of glutamate increased nociceptive acute behavioral responses while DRt lesion by local administration of quinolinic acid had the opposite effect (Almeida et al, 1996).…”

“…Chemical or electrical lesioning of the DRt decrease inflammatory pain behaviors (Almeida et al, 1999). Spino-DRt-spinal excitatory loops are likely involved in the mediation of the pain facilitatory actions observed after formalin injection since both DRt lesioning or blockade of glutamate receptors at the DRt decreases formalin-induced pain behaviors and c-Fos expression in superficial and deep dorsal horn laminae of the spinal cord (Almeida et al, 1999; Ambriz-Tututi et al, 2013). …”