Loss of ICA69 Potentiates Long-Lasting Hyperalgesia After Subcutaneous Formalin Injection into the Mouse Hindpaw

Abstract

Islet-cell autoantigen 69 kDa (ICA69) plays an important role in many diseases and physiological activities by forming heteromeric complexes with protein interacts with C-kinase 1 (PICK1). PICK1 is critical for inflammatory pain hypersensitivity by regulating trafficking of AMPA receptor subunit GluA2 in spinal neurons. However, the role of ICA69 in inflammatory pain has not yet been investigated. Here we reported that expression of PICK1 in spinal cord was reduced largely in ICA69 knockout mice. The pain hypersensitivity was enhanced in the second phase 7 days after formalin administration. Meanwhile, increased Ser880 phosphorylation in GluA2 and decreased surface GluA2 were concordant with the pain. Furthermore, the number of activated microglia in spinal dorsal horn increased in line with pain hypersensitivity. Together, ICA69 deficiency promoted the internalization of GluA2 and FML-induced long-lasting pain hypersensitivity. In addition, microglia activation might be an important factor in the development of the pain hypersensitivity.

Islet-cell autoantigen 69 mediates the antihyperalgesic effects of electroacupuncture on inflammatory pain by regulating spinal glutamate receptor subunit 2 phosphorylation through protein interacting with C-kinase 1 in mice

“…We confirmed that the GluR2-p level significantly increased after CFA injection compared with the Sham group in both ICA69-WT (WT-Sham vs WT-CFA, P < 0.001) and ICA69-KO mice (KO-Sham vs KO-CFA, P < 0.001). Furthermore, the GluR2-p level of the KO-CFA group was significantly increased compared with WT-CFA group ( P = 0.005), which supported that ICA69 KO leads to an increase of GluR2-p. 23 Electroacupuncture reduced the GluR2-p level to the baseline level in WT mice after CFA (WT-CFA vs WT-CFA+EA, P < 0.001), which was related to the analgesic effects confirmed by relevant studies. Electroacupuncture significantly downregulated GluR2-p expression in WT mice but not in ICA69-KO mice (KO-CFA+EA vs WT-CFA+EA, P < 0.001) (Figs.…”

“…ICA69-KO mice show normal spontaneous motor activity compared with their WT littermates (ICA69-WT mice). 23 We performed CFA injection with or without EA treatment on ICA69-KO mice and their WT littermates. There was no significant difference in PWF ( P = 0.195) and PWL ( P = 0.408) between the KO-Sham group and WT-Sham group, indicating that ICA69 KO did not affect the baseline of the plantar pain threshold.…”

“…Our previous investigation showed that the loss of ICA69 increased GluR2 phosphorylation in SDH after subcutaneous formalin injection into the mouse hind paws. 23 To explore the reason why the analgesic effects of EA were weakened in the ICA69-KO mice, we examined the content of GluR2-p, which plays a pivotal role in the spinal transmission of nociceptive information in ICA69-WT and ICA69-KO mice. We confirmed that the GluR2-p level significantly increased after CFA injection compared with the Sham group in both ICA69-WT (WT-Sham vs WT-CFA, P < 0.001) and ICA69-KO mice (KO-Sham vs KO-CFA, P < 0.001).…”

“…The plasma membrane fraction was extracted as described previously. 1,23 In brief, SDH (L3-L5) tissues of mice were homogenized in cold isolation buffer. The homogenate was centrifuged three times as required, and the final precipitation was the the plasma membrane fraction.…”

Dezocine Antagonizes Morphine Analgesia upon Simultaneous Administration in Rodent Models of Acute Nociception

“…Thirty minutes after drug treatment, acute inflammatory pain was induced by subcutaneous injection of 50 µl of 5% formaldehyde into the hind paw dorsum as described by Snijdelaar et al and our previous reports (24,25). This produced a typical flinching and biting response comprising 2 phases: an initial quiescent phase 1 and a prolonged tonic phase 2 beginning about 10 minutes after injection.…”