The expected central targets for pruritoceptors, a subset of C fibers, are dorsal horn neurons located in the upper laminae of the spinal cord. Studies have investigated their potential role as second-order neurons in the itch circuit.
Simone et al. (2004)
saw that most monkey spinothalamic tract (STT) neurons were capsaicin sensitive and a subset of these also responded to histamine. Work in rat (Jinks and Carstens 2002
) found capsaicin also activated dorsal horn neurons responding to the itch mediator serotonin 5HT. Experiments in mouse showed that itch-selective spinal neurons, activated by histamine and 5HT as well as SLIGRL-NH2
, an agonist for the PAR2 receptor, responded to nociceptive stimuli including heat and mustard oil (Akiyama et al., 2009a
). The inhibition of itch by pain was shown in monkey by Davidson et al. (2007a)
, who observed that peripheral scratching inhibited histamine- or cowhage-sensitive STT neurons. They later found a group of histamine- and capsaicin-responsive cells that were inhibited by scratching upon application of the former but not latter compound (Davidson et al., 2009
). These data from different animal models suggest the dual activation of neurons by either itchy or painful stimuli occurs centrally as predicted by selectivity theory. However, there is still debate about the applicability of selectivity versus labeled line theory to itch circuitry in the spinal cord.
In 2001, an STT population responsive to histamine was seen in cat spinal cord, providing early evidence for a potential itch-specific population (Andrew and Craig, 2001
). Certain STT neurons responded only to histamine and not mustard oil, a painful stimulus. The later discovery of a role for the gastrin-releasing peptide receptor (GRPR) in itch (Sun and Chen, 2007
; Sun et al., 2009
) may also mark an itch-specific subset. This receptor is found in the spinal cord dorsal horn, and GRP, the putative ligand, is expressed in some small-diameter DRG neurons. Evoked nonhistaminergic itch, but not pain, is significantly decreased in GRPR mutant mice. When GRPR+
cells are ablated, both histaminergic and nonhistaminergic itch behavior are lost, whereas pain sensitivity is intact. Importantly, in GRPR-ablated lamina I dorsal horn, NK-1+
neurons, most of which are STT neurons required for both pain and itch behavior (see below), are still present, suggesting that GRPR+
and STT neurons comprise two separate populations. The GRPR+
neurons are candidates for the itch-specific spinal cord neurons postulated by labeled line theory. Electrophysiological recordings of these neurons demonstrating that they respond to itchy but not painful stimuli are needed to rule out the possibility that GRPR+
cells play a dispensable role in the pain pathway. It is also important to determine whether GRPR+
cells are projection neurons or interneurons.
Another dorsal horn population expresses NK-1, a G protein-coupled receptor (GPCR) demonstrated to play a critical role in itch produced by 5HT in rat (Carstens et al., 2010
). Removal of NK-1+
neurons also leads to pain deficits (Mantyh et al., 1997
; Nichols et al., 1999
), suggesting this cell population contains the putative pruritoceptors of the selectivity model while also contributing to nociception. It will be interesting to see whether NK-1 overlaps with GRPR in the rat spinal cord and, conversely, whether NK-1 ablation in mouse matches the rat phenotype.
This also raises the important issue of species differences in pruritoception. Even rats, the closest model system to mice, are unique in that histamine does not induce a behavioral scratch response (Jinks and Carstens 2002
). At the level of both DRG (Johanek et al., 2008
; Namer et al., 2008
) and spinal cord (Davidson et al., 2007b
) in humans and nonhuman primates, there seem to be separate C fibers for histaminergic and nonhistaminergic (namely cowhage-induced) itch. Mice, however, demonstrate some overlap with respect to activation by these compounds (Akiyama et al., 2009a
), highlighting another important species difference that must be acknowledged.
The role of spinal interneurons has been the subject of limited study, but a paper from Ross et al. (2010)
identifies a subset of these cells involved in itch. The transcription factor Bhlhb5 is required for development of some dorsal horn neurons. Ablation of this gene from an inhibitory interneuron population marked by Pax2 leads to the development of skin lesions at ~2 months of age in these mice. These results, which parallel those of the VGLUT2 studies, offer a place for spinal interneurons in the itch circuit and call for their further investigation.
A preliminary picture of the pain and itch circuitry emerges from the collective DRG and spinal cord data (). This shows how the selectivity model can explain itch and specifies the molecular identity of certain critical neurons in the pathway.