Biology subjects

Penker, S.

Publications and source records attributed to Penker, S..

3 recordsLinked to original sources

bioRxiv2026

TRPV1-Mediated Delivery of Chloroprocaine, a Local Anesthetic with High pKa, Produces Pain-Selective Anesthesia Without Neurotoxicity

BackgroundConventional local anesthetics (LAs) provide pain relief but also block motor and non-nociceptive fibers, causing undesirable side effects. Approaches using permanently charged derivatives, such as QX-314, delivered via TRPV1 channels, selectively target nociceptors but are limited by neurotoxicity. We hypothesized that clinically approved LAs with high pKa and low toxicity, such as 2-chloroprocaine (chloroprocaine), which is predominantly protonated and membrane-impermeant at physiological pH, would preferentially enter TRPV1-expressing nociceptors when co-administered with a TRPV1 agonist, thereby producing prolonged pain-selective anesthesia without neurotoxicity. MethodsWhole-cell voltage-clamp recordings from rat dorsal root ganglion (DRG) neurons assessed sodium current inhibition. Behavioral experiments in male Sprague-Dawley rats (N=6 -12/group) evaluated sensitivity to noxious thermal and mechanical stimuli and motor function following intraplantar and perisciatic injections of 0.5% or 2% chloroprocaine combined with capsaicin or cannabidiol (CBD). TRPV1 activation was examined by calcium imaging in hTRPV1-expressing HEK293 cells and in capsaicin- and AITC-sensitive DRG neurons. Neurotoxicity was assessed using propidium iodide uptake, long-term behavioral monitoring (35 days), and immunohistochemistry for TRPV1, ATF-3, and GFAP. ResultsCo-application of chloroprocaine with capsaicin enhanced sodium current blockade (76{+/-}15%) compared to either drug alone (p<0.05). Perisciatic injection produced thermal analgesia that persisted for 4 hours, whereas motor block resolved within 30 minutes. Unlike other LAs, chloroprocaine did not activate TRPV1 (98% non-responders) and showed no cytotoxicity. Long-term evaluation revealed no hypersensitivity, neuronal loss, or ATF-3 upregulation. Replacing capsaicin with CBD preserved prolonged ([~] 3.5 h) pain-selective anesthesia without motor impairment. ConclusionsTRPV1-mediated delivery of high-pKa LA chloroprocaine produces prolonged, nociceptor-selective anesthesia without neurotoxicity. Combining a clinically approved high-pKa LAs with low intrinsic toxicity and TRPV1 agonists such as CBD offers a potentially safe strategy for pain-selective regional anesthesia, with implications for perioperative and chronic pain management.

neuroscience↗

bioRxiv2024

Synaptic connectivity and electrophysiological properties of the nucleus of the lateral olfactory tract

The sense of smell is tightly linked to emotions, a link that is thought to rely on the direct synaptic connections between the olfactory bulb and nuclei of the amygdala. A small number of amygdaloid nuclei are the recipients of such direct input from the olfactory bulb and their unique functions are not known. Among them, the nucleus of the lateral olfactory tract (NLOT) is unique in its developmental history and gene expression. NLOT has been very little studied and consequentially its function is unknown. Furthermore, formulation of informed hypotheses about NLOT function is at this stage limited by the lack of knowledge about its connectivity and physiological properties. Here, we used pseudo-rabies tracing methods to systematically reveal monosynaptic inputs into NLOT, and adeno-associated viruses to reveal NLOT projection targets. We found that the NLOT is interconnected with several olfactory brain regions and with the basolateral amygdala. Some of these connections were reciprocal, and some showed unique interhemispheric patterns. We tested the excitable properties of NLOT neurons and the properties of each of the major synaptic inputs. We found that the NLOT receives powerful input from piriform cortex, tenia tecta, and the basolateral amygdala, but only very weak input from the olfactory bulb. When input crosses threshold, NLOT neurons respond with calcium-dependent bursts of action potentials. This integration of olfactory and amygdalar inputs suggests that NLOT plays a role in behaviors that combine smell and emotion, possibly assigning emotional value to odors. Significance statementDespite the well-known functional links between olfaction and emotions, the physiological properties of these links remain largely understudied. One major pathway by which olfactory and emotional signals interact, is via the nucleus of the lateral olfactory tract (NLOT). NLOT has been little studied and its function is yet unclear. The lack of physiological information hinders informed hypotheses. Here, we characterize the synaptic and intrinsic properties of NLOT neurons. We show that the NLOT receives converging olfactory and amygdalar inputs, and that NLOT neurons respond to input with high-rate bursts of action potentials. This suggests that the NLOT, that harbors [~]2500 cells, encodes a low-dimensional signal that is of high importance. We hypothesize that the NLOT assigns emotional value to odors.

neuroscience↗

bioRxiv2019

Reliable readout of mixture components from small populations of piriform cortical neurons

Coding of odorous stimuli has been mostly studied using single isolated stimuli. However, a single sniff of air in a natural environment is likely to introduce airborne chemicals emitted by multiple objects into the nose. The olfactory system is therefore faced with the task of segmenting odor mixtures to identify objects in the presence of rich and often unpredictable backgrounds. The piriform cortex is thought to be the site of object recognition and scene segmentation, yet the nature of its responses to odorant mixtures is largely unknown. In this study, we asked two related questions. 1) How are mixtures represented in the piriform cortex? And 2) Can the identity of individual mixture components be read out from mixture representations in the piriform cortex? To answer these questions, we recorded single unit activity in the piriform cortex of naive mice while sequentially presenting single odorants and their mixtures. We find that a normalization model explains mixture responses well, both at the single neuron, and at the population level. Additionally, we show that mixture components can be identified from piriform cortical activity by pooling responses of a small population of neurons - in many cases a single neuron is sufficient. These results indicate that piriform cortical representations are well suited to perform figure-background segmentation without the need for learning.

neuroscience↗