Although itchiness is a universally annoying sensation, it has yet to be completely figured out. For example, the exact molecular components of the itch pathway are still fuzzy, as is the connection between pain and itch.
In a mini-review published in this month’s Neuron, Kush Patel and Xinzhong Dong of the Hopkins School of Medicine summarize and discuss the most critical findings to date concerning the sensation of itch, also known as pruritus.
These findings include “identification of novel itch receptors besides histamine receptors in primary sensory neurons,” as well as the discovery that “the nerve fibers of primary sensory neurons in dorsal root ganglia are the neurons [that] make initial detection of itch inducing reagents (from outside or inside of the body) in the skin,” according to Dong.
He continues, “Other [recent] works include identification of GRPR+ neurons in dorsal horn neurons in the spinal cord playing essential roles in itch but not pain. These neurons may be (although is not 100%) the secondary neurons receiving itch signals from sensory fibers from DRG [dorsal root ganglion] neurons.”
Two other papers found evidence that glutamate, a neurotransmitter used in pain transmission, is also necessary for itch transmission.
“Together with other findings, people found itch sensing neurons in DRG neurons are a smaller subset of pain-sensing neurons,” Dong said. “The inhibitory interneurons in the spinal cord (Bhlhb5 neurons) [may] provide a cellular mechanism of inhibition of itch pathway by pain pathway.”
Three theories about how itch is encoded by peripheral sensory neurons exist: the labeled line, intensity and selectivity theories.
The labeled line theory involves the existence of separate populations of specific sensory neurons for itch. In other words, pain and itch sensations would not be sensed by the same cells.
This, however, has been shown to not be the case, as a subset of pain-sensing neurons, called nociceptors, have been shown to be sensitive and responsive to itch sensation.
The second model, the intensity theory, accounts for the overlap of pain and itch by saying that the intensity of a sensation felt by these dual-purpose neurons would dictate whether a sensation is felt as either itch or pain.
This model doesn’t quite explain why increasing the intensity of an itchy sensation doesn’t produce the perception of pain, and reducing a painful stimulus’ intensity doesn’t alter perception from pain to itch.
The selectivity theory seems to be the best-fitting model; it accounts not only for the fact that nociceptors can sense itch, but also for the fact that itch sensation can be inhibited by the sensation of pain. According to the model, some nociceptors are also itch receptive, but not all nociceptors can detect both pain and itch.
Activation of those dual-modality sensing cells would lead to the perception of itch, but if a painful stimulus is applied, it would activate all nociceptors, regardless of their ability to sense itchiness, and this would provide the means by which pain can inhibit the sensation of itch.
An interesting twist in the plot comes when one recognizes the role that non-neural cells may play in itch perception (as some non-neural cells play roles in mechanosensation). For instance, Mast cells in the skin have been implicated in itch pathways, as have immune cells, skin cells (keratinocytes), etc.
Using the selectivity theory as a starting point for understanding itch, the molecular mechanisms fall right into place: not only are dual-modality nociceptors different in their response properties from solely pain-sensing neurons, but they also express a receptor shown to play an important role in itch sensation (VGLUT2).
When VGLUT2 is knocked out, mice are much worse at sensing itch, while their pain responses are still quite good. Even more interestingly, when a painful stimulus is applied to dual pain/itch sensing cells and not to their neighboring nociceptors, it is itch that is felt, not pain.
Furthermore, neurons expressing gastrin-releasing peptide (GRP) and MrgprA3 (two markers of itch sensitive cells) overlap with VGLUT2+ cells, which supports VGLUT2’s role in itch sensation.
Conversely, when cells with a receptor called NK-1 are ablated, both pain and itch are impaired; these neurons probably represent the dual-modality nociceptors (which may also be VGLUT2+).
Histamine-mediated itch is perceived via the activity of itch-sensing cells expressing H1 or H4 (histamine) receptors, which, in cooperation with a known pain receptor, TRPV1, can activate a kinase.
On the other hand, non-histaminergic itch is mediated by receptors PAR2 or PAR4 (two pain receptors), which may also interact with TRPV1. This serves to underscore how closely connected are the sensations of pain and itch.
Itch in the spinal cord is still rather poorly understood, especially the role interneurons may play. Some studies have suggested a role for inhibitory interneurons in itch sensation: when these cells are ablated, itch is impaired.
Furthermore, there is also some evidence suggesting that at the level of the spinal cord, there may be itch-only neurons. These neurons have been seen in the spinothalamic tract, which extends from the spine into the thalamus in the brain (a structure involved in sensory relay of information to the cortex); they are responsive to itchy stimuli, but not to a pain-inducing one, mustard oil.
At the level of the spinal cord, it also appears as if there are two different types of itch: histaminergic and non-histaminergic.
Histamine, as many allergy-sufferers will attest, is a powerful, and itchy, irritant. Sensation of histamine-induced itch is reduced when the receptor for gastrin-releasing peptide (GRP) is knocked-out, as is non-histaminergic itch, suggesting that the GRPR may play a critical role in itch sensation (but not in pain sensation, as in GRPR knock-outs, pain sensation is normal).
Interestingly, GRPR and the itch-only spinothalamic tract neurons appear to be different. Thus, two populations of itch-only cells may exist.
Though it is as of yet rather poorly understood, research regarding itch sensation will probably remain active for quite some time, as itch has some clinical importance: treatment with opioids for pain relief can result in overactive and extremely annoying itch sensation (as a result of decreased inhibition by pain pathways, it would appear).
According to Dong, “70 percent of patients taking morphine . . . develop itch as side-effect. So they have to [take] opioid receptor blockers to alleviate itch (but these reduce the analgesic effect of morphine). Similarly, the administration of the anti-malarial drug chloroquine, which is known to activate the aforementioned MgrprA3 receptor, can also induce itch.”
Thus, not only is the study of itch exciting from a purely scientific or neurobiological standpoint, but it also has clinical applications.
