Small
nerve fibers that bind the
isolectin B4 (IB4+ C-fibers) are a subpopulation of primary
afferent neurons that are involved in nociceptive sensory transduction and do not express the
neuropeptides substance P and
calcitonin-
gene related
peptide (CGRP). Several studies have attempted to elucidate the functional
role of IB4+-
nociceptors in different models of
pain. However, a functional characterization of the non-peptidergic
nociceptors in
mediating mechanical inflammatory
hypersensitivity in
mice is still lacking. To this end, in the present study, the
neurotoxin IB4-
Saporin (IB4-Sap) was employed to ablate non-peptidergic C-fibers. Firstly, we showed that intrathecal (i.t.)
administration of IB4-Sap in
mice depleted non-peptidergic C-fibers, since it decreased the expression of
purinoceptor 3 (P2X3) and
transient receptor potential cation channel subfamily V member 1 (TRPV1) in the
dorsal root ganglia (
DRGs) as well as IB4 labelling in the
spinal cord. Non-peptidergic C-fibers depletion did not alter the mechanical nociceptive threshold, but it inhibited the mechanical inflammatory
hypersensitivity induced by
glial cell-derived neurotrophic factor (
GDNF), but not
nerve growth factor (
NGF). Depletion of non-peptidergic C-fibers abrogated mechanical inflammatory
hypersensitivity induced by
carrageenan. Finally, it was found that the inflammatory mediators
PGE2 and
epinephrine produced a mechanical inflammatory
hypersensitivity that was also blocked by depletion of non-peptidergic C-fibers. These data suggest that IB4-positive nociceptive
nerve fibers are not involved in normal mechanical
nociception but are sensitised by inflammatory stimuli and
play a crucial
role in
mediating mechanical inflammatory
hypersensitivity.