Activation of P2X3 receptors in the cerebrospinal fluid-contacting nucleus neurons reduces formalin-induced pain behavior via PAG in a rat model

Abstract Background Systemic administration of oxaliplatin has no effect on the tumors in the central nervous system (CNS) due to the limited concentration of oxaliplatin in the cerebrospinal fluid (CSF), while it was clinically reported that oxaliplatin can induce acute encephalopathy. Currently, the impairment of neuronal functions in the CNS after systemic administration of oxaliplatin remains uninvestigated. Methods The von Frey test and the plantar test were performed to evaluate neuropathic pain behavior after a single intraperitoneal administration of oxaliplatin (4 mg/kg) in rats. Inductively coupled plasma–mass spectrometry, electrophysiologic recording, real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, Western blot, immunohistochemistry, and small interfering RNA were applied to understand the mechanisms. Results Concentration of oxaliplatin in CSF showed a time-dependent increase after a single administration of oxaliplatin. Spinal application of oxaliplatin at the detected concentration (6.6 nM) significantly increased the field potentials in the dorsal horn, induced acute mechanical allodynia (n = 12 each) and thermal hyperalgesia (n = 12 each), and enhanced the evoked excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in the projection neurokinin 1 receptor–expressing lamina I to II neurons. The authors further found that oxaliplatin significantly increased the nuclear factor-κB p65 binding and histone H4 acetylation in cx3cl1 promoter region. Thus, the upregulated spinal CX3CL1 markedly mediated the induction of central sensitization and acute pain behavior after oxaliplatin administration. Conclusions The findings of this study suggested that oxaliplatin in CSF may directly impair the normal function of central neurons and contribute to the rapid development of CNS-related side effects during chemotherapy. This provides novel targets to prevent oxaliplatin-induced acute painful neuropathy and encephalopathy.

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Comparative Efficacies of Antibiotics in a Rat Model of Meningoencephalitis Due to Listeria monocytogenes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.7.1651 ◽

1999 ◽

Vol 43 (7) ◽

pp. 1651-1656 ◽

Cited By ~ 28

Author(s):

Christian Michelet ◽

Stephen L. Leib ◽

Daniele Bentue-Ferrer ◽

Martin G. Täuber

Keyword(s):

Cerebrospinal Fluid ◽

Listeria Monocytogenes ◽

Rat Model ◽

Antibacterial Effect ◽

Antibacterial Activities ◽

The Other ◽

Active Therapy ◽

Treatment Regimens ◽

Infant Rats ◽

The Brain

ABSTRACT The antibacterial activities of amoxicillin-gentamicin, trovafloxacin, trimethoprim-sulfamethoxazole (TMP-SMX) and the combination of trovafloxacin with TMP-SMX were compared in a model of meningoencephalitis due to Listeria monocytogenes in infant rats. At 22 h after intracisternal infection, the cerebrospinal fluid was cultured to document meningitis, and the treatment was started. Treatment was instituted for 48 h, and efficacy was evaluated 24 h after administration of the last dose. All tested treatment regimens exhibited significant activities in brain, liver, and blood compared to infected rats receiving saline (P < 0.001). In the brain, amoxicillin plus gentamicin was more active than all of the other regimens, and trovafloxacin was more active than TMP-SMX (bacterial titers of 4.1 ± 0.5 log10 CFU/ml for amoxicillin-gentamicin, 5.0 ± 0.4 log10 CFU/ml for trovafloxacin, and 5.8 ± 0.5 log10 CFU/ml for TMP-SMX;P < 0.05). In liver, amoxicillin-gentamicin and trovafloxacin were similarly active (2.8 ± 0.8 and 2.7 ± 0.8 log10 CFU/ml, respectively) but more active than TMP-SMX (4.4 ± 0.6 log10 CFU/ml; P< 0.05). The combination of trovafloxacin with TMP-SMX did not alter the antibacterial effect in the brain, but it did reduce the effect of trovafloxacin in the liver. Amoxicillin-gentamicin was the most active therapy in this study, but the activity of trovafloxacin suggests that further studies with this drug for the treatment ofListeria infections may be warranted.

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