IL‐1beta in the trigeminal subnucleus caudalis contributes to extra‐territorial allodynia/hyperalgesia following a trigeminal nerve injury

It has been reported that the whisker pad (WP) area, which is innervated by the second branch of the trigeminal nerve, shows allodynia/hyperalgesia following transection of the mental nerve (MN: the third branch of the trigeminal nerve). However, the mechanisms of this extra‐territorial pain induction still remain unclear. Glia and cytokines are known to facilitate perception of noxious input, raising a possibility that these non‐neuronal elements are involved in the induction and spread of allodynia/hyperalgesia at non‐injured skin territory. One day after MN transection, tactile allodynia/hyperalgesia developed on the ipsilateral WP area, which is in the non‐injured skin territory. The tactile allodynia/hyperalgesia lasted for more than 56 days. In response to MN transection, astrocytes and microglia appeared to be in an activated state, and interleukin (IL)‐1beta was up‐regulated in astrocytes in the trigeminal subnucleus caudalis (Vc). Allodynia/hyperalgesia at WP area induced by MN transection was attenuated dose‐dependently by IL‐1 receptor antagonist IL‐1ra (i.t., 0.05, 0.5, and 5pg/rat). Fos‐like immunoreactive (Fos‐Li) neurons were observed in the Vc after non‐noxious mechanical stimulation of the WP area in the rats with MN transection. Administration of IL‐1ra also attenuated the number of Fos‐Li neurons dose‐dependently. Administration of a noncompetitive antagonist of NMDA receptors MK‐801 (i.t., 5μg/rat) reversed allodynia/hyperalgesia. IL‐1 receptor type I (IL‐1RI) was localized in Fos‐ and phospho NR1‐immunoreactive neurons. These results suggest that IL‐1beta in the Vc plays an important role in the development of extra‐territorial tactile allodynia/hyperalgesia after MN transection.