Spinal Toll like Receptor 3 is Involved in Chronic Pancreatitis-Induced Mechanical Allodynia of Rat

Abstract

BackgroundMechanisms underlying pain in chronic pancreatitis (CP) are incompletely understood. Our previous data showed that astrocytes were actively involved. However, it was unclear how astrocytic activation was induced in CP conditions. In the present study, we hypothesized that toll-like receptors (TLRs) were involved in astrocytic activation and pain behavior in CP-induced pain.ResultsTo test our hypothesis, we first investigated the changes of TLR2-4 in the rat CP model induced by intrapancreatic infusion of trinitrobenzene sulfonic acid (TNBS). Western blot showed that after TNBS infusion, TLR3, but not TLR2 or TLR4, was increased gradually and maintained at a very high level for up to 5 w, which correlated with the changing course of mechanical allodynia. Double immunostaining suggested that TLR3 was highly expressed on astrocytes. Infusion with TLR3 antisense oligodeoxynucleotide (ASO) dose-dependently attenuated CP-induced allodynia. CP-induced astrocytic activation in the spinal cord was also significantly suppressed by TLR3 ASO. Furthermore, real-time PCR showed that IL-1β, TNF-α, IL-6 and monocyte chemotactic protein-1 (MCP-1) were significantly increased in spinal cord of pancreatic rats. In addition, TLR3 ASO significantly attenuated CP-induced up-regulation of IL-1β and MCP-1.ConclusionsThese results suggest a probable "TLR3-astrocytes-IL-1β/MCP-1" pathway as a positive feedback loop in the spinal dorsal horn in CP conditions. TLR3-mediated neuroimmune interactions could be new targets for treating persistent pain in CP patients.

Spinal Cord Toll-Like Receptor 4 Mediates Inflammatory and Neuropathic Hypersensitivity in Male But Not Female Mice

“…Even among TLRs, TLR2 (Kim et al, 2007) and TLR3 (Qian et al, 2011) have also been implicated in chronic pain development. Thus, it is perhaps not surprising that Tlr4 null mutant B10ScNJ mice displayed equipotent allodynia from CFA and SNI compared to wildtype B10ScSnJ, although this finding is in direct contrast to those of Tanga and colleagues (2005).…”

Pattern recognition receptors in chronic pain: Mechanisms and therapeutic implications

“…Intrathecal injection of TLR3 antisense ODN suppresses spinal nerve injury-induced mechanical allodynia in mice (Obata et al, 2008). TLR3 antisense ODN has also been shown to attenuate mechanical allodynia induced by intrapancreatic infusion of trinitrobenzene sulfonic acid (TNBS)-induced chronic pancreatitis model in rats (Qian et al, 2011). Intraperitoneal injection of ODN2088, a suppressive ODN of TLR9, blocked the development of thermal hyperalgesia induced by the inoculation of tumour cells into the muscular tissue in the vicinity of the sciatic nerve in mice (Qi et al, 2011).…”

Neural plasticity in pancreatitis and pancreatic cancer

“…For pancreatic cancer, Imoto et al 46 injected human pancreatic cancer cells into the sciatic nerve of severe combined immunodeficient mice and detected increased astrocytic activity in the ipsilateral dorsal horn (see Figure 2 for detail of relevant CNS anatomy). For chronic pancreatitis, Qian et al 68 measured increased mechanical allodynia (pain resulting from a stimulus that would not normally provoke pain) in the TNBS model of chronic pancreatitis, which was associated with increased astrocytic Toll-like receptor (TLR)3 expression and reversible upon administration of TLR3 antisense oligodeoxynucleotide. Liu et al 69 showed increased nocifensive behaviour and spinal microglial activity in rats with TNBS-induced chronic pancreatitis, which were reversible upon intrathecal administration of the microglial inhibitor minocycline.…”