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.