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Fast-conducting mechanoreceptors contribute to withdrawal behavior in normal and nerve injured rats.

ABSTRACT: Fast-conducting myelinated high-threshold mechanoreceptors (AHTMR) are largely thought to transmit acute nociception from the periphery. However, their roles in normal withdrawal and in nerve injury-induced hyperalgesia are less well accepted. Modulation of this subpopulation of peripheral neurons would help define their roles in withdrawal behaviors. The optically active proton pump, ArchT, was placed in an adeno-associated virus-type 8 viral vector with the CAG promoter and was administered by intrathecal injection resulting in expression in myelinated neurons. Optical inhibition of peripheral neurons at the soma and transcutaneously was possible in the neurons expressing ArchT, but not in neurons from control animals. Receptive field characteristics and electrophysiology determined that inhibition was neuronal subtype-specific with only AHTMR neurons being inhibited. One week after nerve injury the AHTMR are hyperexcitable, but can still be inhibited at the soma and transcutaneously. Withdrawal thresholds to mechanical stimuli in normal and in hyperalgesic nerve-injured animals also were increased by transcutaneous light to the affected hindpaw. This suggests that AHTMR neurons play a role not only in threshold-related withdrawal behavior in the normal animal, but also in sensitized states after nerve injury. This is the first time this subpopulation of neurons has been reversibly modulated to test their contribution to withdrawal-related behaviors before and after nerve injury. This technique may prove useful to define the role of selective neuronal populations in different pain states.

SUBMITTER: Boada MD

PROVIDER: S-EPMC4374598 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Fast-conducting mechanoreceptors contribute to withdrawal behavior in normal and nerve injured rats.

Boada Danilo M DM Martin Thomas J TJ Peters Christopher M CM Hayashida Kenichiro K Harris Michael H MH Houle Timothy T TT Boyden Edward S ES Eisenach James C JC Ririe Douglas G DG

Pain 20140928 12

Fast-conducting myelinated high-threshold mechanoreceptors (AHTMR) are largely thought to transmit acute nociception from the periphery. However, their roles in normal withdrawal and in nerve injury-induced hyperalgesia are less well accepted. Modulation of this subpopulation of peripheral neurons would help define their roles in withdrawal behaviors. The optically active proton pump, ArchT, was placed in an adeno-associated virus-type 8 viral vector with the CAG promoter and was administered by ...[more]

PMID: 25267211

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Project description:Cinobufotalin is one of the major anti-tumor components isolated from toad venom and has been used in the clinical therapy of hepatocellular carcinoma (HCC), known as Cinobufacini injection. However, the pharmacokinetic (PK) behaviors of cinobufotalin in vivo with HCC are still unknown. Hence, we have established a HCC model in Sprague Dawley (SD) rats induced by diethylnitrosamine (DEN), named as DEN-injured rats. Then, we developed and validated a sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify cinobufotalin in rat plasma. This UPLC-MS/MS method was successfully used to characterize the PK behaviors of cinobufotalin in normal and DEN-injured rats after intravenous (i.v.) injection at a dosage of 2.5 mg/kg. Cinobufotalin pharmacokinetics was well described by the two-compartment pharmacokinetic model and the PK parameters were calculated using WinNonlin 3.3 software. The transfer rate constant of cinobufotalin from the central compartment to the peripheral compartment (k12) in DEN-injured rats was significantly greater than that in normal rats (p < 0.01), accompanied by the shorter half-life for the distribution phase (t1/2α). Additionally, the elimination rate constant (K10) and clearance (CL) values in DEN-injured rats were significantly higher than that in normal rats (p < 0.05 for K10 and p < 0.001 for CL, respectively). Therefore, the values of areas under concentration - time curve (AUC) and the liver concentration of cinobufotalin in DEN-injured rats was obviously lower than that in normal rats (p < 0.001 and p < 0.01, respectively). This indicated that the PK behaviors of cinobufotalin will be altered in rats with HCC. In addition, P-glycoprotein (P-gp) has shown higher expression in live tissues of DEN-injured rats. Furthermore, cinobufotalin was identified as the substrate of P-gp using MDCK II and MDCK-MDR1 cell models for the first time. Consequently, P-gp will play an important role in the disposition of cinobufotalin in vivo, which provided a new combination therapy for the clinical treatment of HCC.

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Fast-conducting mechanoreceptors contribute to withdrawal behavior in normal and nerve injured rats.

Publications

Fast-conducting mechanoreceptors contribute to withdrawal behavior in normal and nerve injured rats.

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