Abstract
In the present study, we used functional MRI in awake rats to investigate the pain response that accompanies intradermal injection of capsaicin into the hindpaw. To this end, we used BOLD imaging together with a 3D segmented, annotated rat atlas and computational analysis to identify the integrated neural circuits involved in capsaicin-induced pain. The specificity of the pain response to capsaicin was tested in a transgenic model that contains a biallelic deletion of the gene encoding for the transient receptor potential cation channel subfamily V member 1 (TRPV1). Capsaicin is an exogenous ligand for the TRPV1 receptor, and in wild-type rats, activated the putative pain neural circuit. In addition, capsaicin-treated wild-type rats exhibited activation in brain regions comprising the Papez circuit and habenular system, systems that play important roles in the integration of emotional information, and learning and memory of aversive information, respectively. As expected, capsaicin administration to TRPV1-KO rats failed to elicit the robust BOLD activation pattern observed in wild-type controls. However, the intradermal injection of formalin elicited a significant activation of the putative pain pathway as represented by such areas as the anterior cingulate, somatosensory cortex, parabrachial nucleus, and periaqueductal gray. Notably, comparison of neural responses to capsaicin in wild-type vs. knock-out rats uncovered evidence that capsaicin may function in an antinociceptive capacity independent of TRPV1 signaling. Our data suggest that neuroimaging of pain in awake, conscious animals has the potential to inform the neurobiological basis of full and integrated perceptions of pain.
Highlights
The transient receptor potential vanilloid 1 (TRPV1) channel is a polymodal receptor critical to the sensing of noxious heat (>43◦C), bidirectional changes in pH, and capsaicin, amongst a variety of other stimuli (Szallasi et al, 2007)
The current study seeks to elucidate the neural response to peripherally administered capsaicin by employing functional magnetic resonance imaging in awake rats lacking TRPV1 receptors
Activation maps depicting the location of the positive BOLD signal change in a 3D rendering of the pain neural circuit, or in 2D axial sections from the rat atlas, illustrate the regions activated by capsaicin in wild-type rats
Summary
The transient receptor potential vanilloid 1 (TRPV1) channel is a polymodal receptor critical to the sensing of noxious heat (>43◦C), bidirectional changes in pH, and capsaicin, amongst a variety of other stimuli (Szallasi et al, 2007). Shown is a truncated list of 137 brain areas and their median (med, gray highlight), maximum (max) and minimum (min) number of voxels activated at 3–5 min post-intradermal injection of vehicle, capsaicin and formalin into the hindpaw of TRPV1 knockout rats.
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