Background: Chronic pancreatitis (CP) is a long-standing inflammation of the exocrine pancreas,
which typically results in severe and constant abdominal pain. Previous studies on the mechanisms
underlying CP-induced pain have primarily focused on the peripheral nociceptive system. A role
for a central mechanism in the mediation or modulation of abdominal pain is largely unknown.
Tanshinone IIA (TSN IIA), an active component of the traditional Chinese medicine Danshen, exhibits
anti-inflammatory properties via downregulation of the expression of high-mobility group protein
B1 (HMGB1), a late proinflammatory cytokine. HMGB1 binds and activates toll-like receptor 4 (TLR4)
to induce spinal astrocyte activation and proinflammatory cytokine release in neuropathic pain.
Objective: In this study, we investigated the effect of TSN IIA on pain responses in rats with
trinitrobenzene sulfonic acid (TNBS)-induced CP. The roles of central mechanisms in the mediation
or modulation of CP were also investigated.
Study Design: A randomized, double-blind, placebo-controlled animal trial.
Methods: CP was induced in rats by intrapancreatic infusion of trinitrobenzene sulfonic acid
(TNBS). Pancreatic histopathological changes were characterized with semi-quantitative scores. The
abdomen nociceptive behaviors were assessed with von Frey filaments. The effects of intraperitoneally
administered TSN IIA on CP-induced mechanical allodynia were tested. The spinal protein expression of
HMGB1 was determined by western blot. The spinal mRNA and protein expression of proinflammatory
cytokines IL-1β, TNF-α, and IL-6 were determined by RT-PCR and western blot, respectively. The spinal
expression of the HMGB1 receptor TRL4 and the astrocyte activation marker glial fibrillary acidic
protein (GFAP) were determined by western blot or immunohistological staining after intraperitoneal
injection of TSN IIA or intrathecal administration of a neutralizing anti-HMGB1 antibody.
Results: TNBS infusion resulted in pancreatic histopathological changes of chronic pancreatitis
and mechanical allodynia in rats. TSN IIA significantly attenuated TNBS-induced mechanical
allodynia in a dose-dependent manner. TNBS significantly increased the spinal expression of
HMGB1 and proinflammatory cytokines IL-1β, TNF-α, and IL-6. These TNBS-induced changes
were significantly inhibited by TSN IIA in a dose-dependent manner. Furthermore, TSN IIA, but
not the neutralizing anti-HMGB1 antibody, significantly inhibited TNBS-induced spinal TLR4 and
GFAP expression.
Limitations: In addition to TLR4, HMGB1 can also bind to toll-like receptor-2 (TLR2) and
the receptor for advanced glycation end products (RAGE). Additional studies are warranted to
ascertain whether HMGB1 contributes to CP-induced pain through activation of these receptors.
Conclusions: Our results suggest that spinal HMGB1 contributes to the development of CPinduced pain and can potentially be a therapeutic target. TSN IIA attenuates CP-induced pain via
downregulation of spinal HMGB1 and TRL4 expression. Therefore, TSN IIA may be a potential
anti-nociceptive drug for the treatment of CP-induced pain.
Key words: Chronic pancreatitis, HMGB1, proinflammatory cytokine, Tanshinone IIA, spinal
cord, astrocyte, TLR4
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