Paclitaxel-induced increase in mitochondrial volume mediates dysregulation of intracellular Ca in putative nociceptive glabrous skin neurons from the rat.

We have recently demonstrated that in a rat model of chemotherapy-induced peripheral neuropathy (CIPN), there is a significant decrease in the duration of the depolarization-evoked Ca transient in small diameter, IB4+, and capsaicin-responsive neurons innervating the glabrous skin of the hindpaw. This change was specific to the transient duration and significantly smaller if not undetectable in neurons innervating the dorsal skin of the hindpaw or the skin of the inner thigh. Given the importance of mitochondria in intracellular Ca regulation and the findings of chemotherapy-associated increase in mitotoxicity along the sensory neuron axons, we hypothesized that CIPN is due to both increases and decreases in mitochondria function, with changes manifest in distinct subpopulations of afferents.

Paclitaxel-induced increase in NCX activity in subpopulations of nociceptive afferents: A protective mechanism against chemotherapy-induced peripheral neuropathy?

We recently demonstrated, in a rat model of chemotherapy-induced peripheral neuropathy (CIPN), that there is a significant decrease in the duration of the depolarization-evoked Ca(2+) transient in isolated somata of putative nociceptive afferents innervating the glabrous skin of the hindpaw, but no change in transient magnitude or the resting concentration of intracellular Ca(2+) ([Ca(2+)]i). Because the Na(+)-Ca(2+) exchanger (NCX) only contributes to the regulation of the duration of the evoked Ca(2+) transient, in putative nociceptive dorsal root ganglion (DRG) neurons, we hypothesized that an increase in NCX activity underlies the CIPN-induced change in this subpopulation of neurons. Acutely dissociated retrogradely labeled sensory neurons from naïve, vehicle-, and paclitaxel-treated rats were studied with fura-2 based Ca(2+) imaging.

Mechanisms underlying midazolam-induced peripheral nerve block and neurotoxicity.

Background And Objectives: The benzodiazepine midazolam has been reported to facilitate the actions of spinally administrated local anesthetics. Interestingly, despite the lack of convincing evidence for the presence of γ-aminobutyric acid type A (GABAA) receptors along peripheral nerve axons, midazolam also has been shown to have analgesic efficacy when applied alone to peripheral nerves.These observations suggest midazolam-induced nerve block is due to another site of action.

Heme oxygenase-1 protects human hepatocytes in vitro against warm and cold hypoxia.

Background/aims: Hepatic injury induced by ischemia/reperfusion following surgery, transplantation, or circulatory shock combined with resuscitation is a major clinical problem.

Methods: In this study, hypoxic and inflammatory conditions were mimicked by exposing human hepatocytes to N(2) (at 4 and 37 degrees C) or to cytokines/endotoxin to investigate the potential protective effects of heme oxygenase-1 (HO-1). Incubation of human hepatocytes with single cytokines (IFN-gamma, IL-1beta, TNF-alpha) or LPS, as well as a combination of all four stimuli (CM, cytomix) caused a time-dependent HO-1 mRNA expression over 12h and a decline by 24 h.