016P Queen Elizabeth II Conference Centre London
Pharmacology 2014

 

 

High mobility group box 1 as a target for prevention and therapeutic treatment of chemotherapy-induced neuropathic pain

Atsufumi Kawabata1, Yudai Kawaishi1, Takeshi Nishida1,2, Hiroki Yamanishi1, Natsuki Kamitani1, Maho Tsubota1, Fumiko Sekiguchi1, Hiroyasu Ishikura2, Masahiro Nishibori3. 1Kinki University School of Pharmacy, Higashi-Osaka, Japan, 2Fukuoka University Hospital, Fukuoka, Japan, 3Okayama University Graduate School of Medicine, Okayama, Japan

High mobility group box 1 (HMGB1), a nuclear protein, is included in damage-associated molecular patterns (DAMPs). We have demonstrated the involvement of HMGB1 in inflammatory somatic (1) and bladder (2) pain signalling. There is also evidence for involvement of HMGB1 in neuropathic pain induced by spinal nerve ligation (3). Here we describe the role of HMGB1 in the development and maintenance of chemotherapy-induced neuropathic pain.

The mechanical nociceptive threshold in adult male Wistar rats was measured by the paw pressure test. Neuropathic pain was induced by 4 repeated i.p. doses of paclitaxel (PTX) at 2 mg/kg/2 days and by 2 cycles of 5 repeated i.p. doses of vincristine (VCT) at 0.1 mg/kg/day with 2-day break. Anti-HMGB1 neutralising antibody was repeatedly administered i.p. 30 min before each dose of PTX or VCT, or given i.p. once after the establishment of neuropathic pain (14 days after the onset of PTX or VCT treatment).

Repeated administration of the anti-HMGB1 neutralising antibody prevented the development of neuropathic pain induced by PTX or VCT in rats (Table 1). A single administration of the anti-HMGB1 antibody also reversed the established neuropathic pain induced by PTX or VCT (Table 1).

Table 1 Prevention and reversal by anti-HMGB1 neutralising antibody of chemotherapy-induced neuropathic pain (NP) in rats

Anti-cancer drug Treatment with the antibody or non-immune IgG Repeated treatment during NP development (Threshold at day 14) Single treatment after NP establishment (Threshold 1 h after treatment with PBS, IgG or antibody)
Vehicle PBS 97.5 ± 2.4 (4) 103.0 ± 2.8 (7)
PTX Non-immune IgG 69.0* ± 3.3 (5) 65.0* ± 1.7 (6)
PTX Anti-HMGB1 91.8† ± 2.4 (5) 94.7† ± 3.4 (6)
Vehicle PBS 106.1 ± 7.5 (6) 104.8 ± 1.3 (4)
VCT Non-immune IgG 72.5* ± 3.8 (5) 66.8* ± 3.3 (6)
VCT Anti-HMGB1 117.7† ± 7.4 (6) 110.9† ± 3.2 (6)

Data show means±s.e.m. of mechanical nociceptive threshold (% of the baseline value). Parentheses indicate the number of rats. *P<0.05 vs. Vehicle + PBS, †P<0.05 vs. PTX or VCT + non-immune IgG.

In summary, HMGB1 is involved in the pathogenesis of neuropathic pain induced by PTX or VCT, and also plays a role in maintenance of the chemotherapy-induced neuropathic pain. HMGB1 is thus considered a target for prevention and/or therapeutic treatment of chemotherapy-induced neuropathy.

(1) Tanaka J et al. (2013) Br J Pharmacol 170: 1233-1241.

(2) Tanaka J et al. (2014) Neuropharmacology 79: 112-118.

(3) Shibasaki M et al. (2010) Pain 149: 514-521.