Abstract
The limited success of translating basic animal findings into effective clinical treatments of pain can be partly ascribed to the use of sub-optimal models. Murine models of pain often consist in recording (1) threshold responses (like the tail-flick reflex) elicited by (2) non-nociceptive specific inputs in (3) anaesthetized animals. The direct cortical recording of laser-evoked potentials (LEPs) elicited by stimuli of graded energies in freely-moving rodents avoids these three important pitfalls, and has thus the potential of improving such translation. Murine LEPs are classically reported to consist of two distinct components, reflecting the activity of Aδ- and C-fibre afferent pathways. However, we have recently demonstrated that the so-called “Aδ-LEPs” in fact reflect the activation of the auditory system by laser-generated ultrasounds. Here we used ongoing white noise to avoid the confound represented by the early auditory response, and thereby comprehensively characterized the physiological properties of C-fibre LEPs recorded directly from the exposed surface of the rat brain. Stimulus–response functions indicated that response amplitude is positively related to the stimulus energy, as well as to nocifensive behavioral score. When displayed using average reference, murine LEPs consist of three distinct deflections, whose polarity, order, and topography are surprisingly similar to human LEPs. The scalp topography of the early N1 wave is somatotopically-organized, likely reflecting the activity of the primary somatosensory cortex, while topographies of the later N2 and P2 waves are more centrally distributed. These results indicate that recording LEPs in freely-moving rats is a valid model to improve the translation of animal results to human physiology and pathophysiology.
Highlights
Pain is an increasingly important healthcare issue, with dramatic costs for both patient wellbeing and the society (Breivik et al, 2008)
Considering that the electrocortical responses elicited by nociceptive stimuli are widely used to study pain in healthy individuals and patients (Cruccu et al, 2008; Haanpaa et al, 2011; Treede et al, 2003), the use of similar setups in animal and human studies presents the additional advantage of facilitating successful translation
We recently showed that the early part of the cortical response elicited by laser stimulation reflects the ultrasound-induced activation of the auditory system and not, as previously thought, of the Aδ-nociceptive pathways (Hu et al, 2015)
Summary
Pain is an increasingly important healthcare issue, with dramatic costs for both patient wellbeing and the society (Breivik et al, 2008). Somatosensory stimuli that are neither nociceptive-specific nor quantifiable (e.g., pinching or heating the skin with hot water) (Bastos and Tonussi, 2010; Hernandez et al, 1994; Toda et al, 2008; Uchida et al, 2012), (2) the recording of ‘threshold’ measures (e.g., the tail-flick reflex), instead of suprathreshold responses that allow deriving stimulus–response functions (Carstens and Wilson, 1993; Danneman et al, 1994), and (3) the use of anaesthetized animals when the neural activity of the central nervous system is sampled using electrophysiology or functional magnetic resonance imaging (Ando et al, 2004; Becerra et al, 2011; Toda et al, 2008; Yen and Shaw, 2003) These three important issues can be satisfactorily addressed by combining the selective laser stimulation of skin nociceptors with the recording of the cortical activity using electrodes placed directly on the exposed surface of the brain (electrocorticography, ECoG) in freely-moving rats. Considering that the electrocortical responses elicited by nociceptive stimuli (laser-evoked potentials, LEPs) are widely used to study pain in healthy individuals and patients (Cruccu et al, 2008; Haanpaa et al, 2011; Treede et al, 2003), the use of similar setups in animal and human studies presents the additional advantage of facilitating successful translation
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