Pain behavior in the formalin test persists after ablation of the great majority of C-fiber nociceptors.
Although the formalin test is a widely used model of persistent pain, the primary afferent fiber types that underlie the cellular and behavioral responses to formalin injection are largely unknown. Here we used a combined genetic and pharmacological approach to investigate the effect of ablating subsets of primary afferent nociceptors on formalin-induced nocifensive behaviors and spinal cord Fos protein expression. Intrathecal capsaicin-induced ablation of the central terminals of TRPV1+neurons greatly reduced the behavioral responses and Fos elicited by low-dose (0.5%) formalin. In contrast, genetic ablation of the MrgprD-expressing subset of non-peptidergic unmyelinated afferents, which constitute a largely non-overlapping population, altered neither the behavior nor the Fos induced by low-dose formalin. Remarkably, nocifensive behavior following high-dose (2%) formalin was unchanged in mice lacking either afferent population, or even in mice lacking both populations, which together make up the great majority of C-fiber nociceptors. Thus, at high doses, which are routinely used in the formalin test, formalin-induced "pain" behavior persists in the absence of the vast majority of C-fiber nociceptors, which points to a contribution of a large spectrum of afferents secondary to non-specific formalin-induced tissue and nerve damage.
Shields
Shannon D
SD
Depts of Anatomy and Physiology and WM Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, CA, USA Division of Biology and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, USA.
Cavanaugh
Daniel J
DJ
Lee
Hyosang
H
Anderson
David J
DJ
Basbaum
Allan I
AI
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D020169:Caspases / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009149:Mustard Plant / Q000009:adverse effects; D036421:Nerve Fibers, Unmyelinated / Q000378:metabolism / Q000473:pathology*; D009619:Nociceptors / Q000473:pathology*; D010146:Pain / Q000139:chemically induced / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D010147:Pain Measurement; D010938:Plant Oils / Q000009:adverse effects; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology*; D050916:TRPV Cation Channels / Q000172:deficiency / Q000378:metabolism; D013997:Time Factors
C497098:Mrgprd protein, mouse; D010938:Plant Oils; D043562:Receptors, G-Protein-Coupled; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D005557:Formaldehyde; D020169:Caspases; C027793:mustard oil