Imaging the influence of peripheral TRPV1-signaling on cerebral nociceptive processing applying fMRI-based graph theory in a resiniferatoxin rat model

Abstract

Resiniferatoxin (RTX), an extract from the spurge plant Euphorbia resinifera, is a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), mainly expressed on peripheral nociceptors—a prerequisite for nociceptive heat perception. Systemic overdosing of RTX can be used to desensitize specifically TRPV1-expressing neurons, and was therefore utilized here to selectively characterize the influence of TRPV1-signaling on central nervous system (CNS) temperature processing. Resting state and CNS temperature processing of male rats were assessed via functional magnetic resonance imaging before and after RTX injection. General linear model-based and graph-theoretical network analyses disentangled the underlying distinct CNS circuitries. At baseline, rats displayed an increase of nociception-related response amplitude and activated brain volume that correlated highly with increasing stimulation temperatures. In contrast, RTX-treated rats showed a clear disruption of thermal nociception, reflected in a missing increase of CNS responses to temperatures above 48°C. Graph-theoretical analyses revealed two distinct brain subnetworks affected by RTX: one subcortical (brainstem, lateral and medial thalamus, hippocampus, basal ganglia and amygdala), and one cortical (primary sensory, motor and association cortices). Resting state analysis revealed first, that peripheral desensitization of TRPV1-expressing neurons did not disrupt the basic resting-state-network of the brain. Second, only at baseline, but not after RTX, noxious stimulation modulated the RS-network in regions associated with memory formation (e.g. hippocampus). Altogether, the combination of whole-brain functional magnetic resonance imaging and RTX-mediated desensitization of TRPV1-signaling provided further detailed insight into cerebral processing of noxious temperatures.

The impact of HCN4 channels on CNS brain networks as a new target in pain development

“…As these results showed highly significant differences between HCN4-KO and Ctr at the stimulation temperature of 45°C, we next focused on this temperature as well as the next higher temperature of 50°C. This was not chosen arbitrarily, as we know that the threshold between warmth and heat detection in rodent thermal fMRI lies between these two temperatures ( Wank et al, 2022 ). This allowed us to obtain information about thermal discrimination and nociceptive processing simultaneously without having to account for endogenous descending inhibition, which is thought to be active at around 54°C.…”

“…As transient thermal stimulation is known to modulate RS FC ( Kreitz et al, 2018 ; Wank et al, 2022 ), we also performed RS measurements directly before and after the stimulus-driven fMRI measurement to investigate the short-term modulatory influence of thermal stimuli on basic resting brain function. Since no significant differences were found between HCN4-KO and Ctr in the pre RS measurement, this leads to the conclusion that the brain-specific knockout of HCN4 does not affect basic resting brain function in general.…”