By Nathifa Nasim, Neurobiology, Physiology & Behavior ‘22
Author’s Note: Itch is not a stranger to any of us, but growing up with eczema, I have always been hyper aware of it. As far back as I can remember, burning hot showers and painful levels of scratching temporarily alleviated the maddening sensation of itch without my understanding of how pain was linked to itch. Once I joined the Carstens Lab studying the relationship between itch and pain, these memories were rekindled, and I became interested in not only understanding itch, which we know so little of, but how these two sensations interact. This paper was also written for my UWP 104E class.
Itch is an everyday sensation that nearly all people have experienced. Its origins lie in its role as a defense mechanism — when faced with irritant stimuli, the scratching urge produced by itch can remove potentially harmful substances . However, despite its evolutionary advantages, itch is often a source of discomfort and for many can dramatically impact their quality of life. Itch not only includes acute itch such as mosquito bites, but debilitating chronic itch can stem from different diseases such as cancer, HIV/AIDS, liver/kidney failure, atopic dermatitis, and other skin disorders . However, despite the widespread impacts of itch, much of its mechanisms and pathways still remain elusive.
Itch is a somatosensory sensation, relying on the nervous system for detection and perception, therefore similar to other somatosensory sensations such as heat, touch, vibration, and most importantly, pain. Pain and itch have an antagonistic relationship, meaning each sensation has an opposing effect on the other. This is evident in “painful” scratching which relieves the feeling of itch, and that morphine administration reduces pain while increasing itch . The intersection between the two sensations translates to potential treatment as well: chronic itch, for example, can be treated by medications similar to chronic pain . Researching the interplay between itch and pain can help illuminate the pathophysiology of itch and how it is perceived as a sensation different from pain, and consequently lead to a better understanding of treating itch.
Currently, there are numerous models and theories proposed to explain this overlap, however, there is no consensus amongst itch researchers on which model(s) may best explain the relationship between pain and itch. This review will be an overview of the various models of itch transduction and perception and how they have evolved with the accumulation of new research. It will also cover the basic mechanisms of itch at the level of the periphery and spinal cord and how it interacts with pain.
Overview of Itch Mechanisms
Itch Activation at the Level of the Epidermis
Pruriceptors are neurons capable of detecting itch; these can be activated by either mechanical stimuli, a scratchy fabric for instance, or chemical stimuli, such as poison ivy. For simplicity, and as the chemical pathway is currently better understood, the paper will focus on chemical itch from here onwards. Similar to other somatosensory neurons, the cell bodies of the primary pruriceptive neurons reside in the dorsal root ganglion (DRG), close to the spinal cord, with axons stretching to both the periphery and the spinal cord [4, 5]. Unlike other sensory modalities, itch is specific to the outermost epidermis only, as opposed to pain, which can be felt in the muscle and bone. The pruriceptors’ branched sensory nerve endings which terminate in the epidermis are studded with membrane receptors activated by various “itchy” mediators . The receptors differ in the mediators they respond to but can be broadly grouped into histamine receptors, serotonin receptors, G Protein-coupled receptors (GPCRs), toll-like receptors (TLRs), or cytokine and chemokine receptors [4,5].
Once acute itch is triggered by an irritant, keratinocytes, mast cells, and immune cells release chemical mediators which trigger vasodilation, inflammation, and the arrival of more immune cells to clear the irritant. The chemical mediators can include histamine, serotonin, proteases, cytokines, and chemokines, each of which is associated with a certain receptor . The activation of itch from internal factors in disease differs from acute itch in that it is instead dependent on unknown mediators in the bloodstream from drugs or diseased organs . Despite the origin of the chemical mediators, however, once released they bind to the receptors on the free nerve endings and activate them. The receptors then depend on various ion channels to depolarize the pruriceptor neuron which conveys the sensory information to the spinal cord via its axon [4, 5].
Itch Transmission to the Spinal Cord
The pruriceptive DRG neurons’ axon also ends in the spinal dorsal horn. These then synapse onto interneurons in the spinal cord which connect to projection neurons that carry the sensory information to the brain. The interneurons are important for transmission as well as modulation of itch via excitatory and inhibitory synapses [4, 5, 6]. Electrophysiological responses to itch stimuli in primates have identified the projection neurons as belonging to the spinothalamic tract, which carries axons to the thalamus. This tract also conveys pain and temperature and is consequently an area of itch interaction with other modalities [5, 7]. In addition to interneurons, descending modulation in the spinal cord can also regulate itch. After applying a cervical cold block to mice – activity of the upper cervical spinal cord level was essentially stopped – mice were unable to relieve itch and decrease neuronal firing when the lumbar spinal cord neurons below were stimulated by an itchy substance. This suggests that there is some level of descending modulation that was disrupted when the upper spinal cord was damaged .
Areas of Itch and Pain Interaction
Having briefly discussed the pathways for itch perception, it is important to note how often it converges with that of pain. Firstly, pruriceptors are in fact pruriceptive nociceptive neurons, meaning they are a subset of nociceptors, or pain-sensitive neurons. Although there are many non-pruriceptive nociceptors (neurons sensitive to pain but not itch), studies have pointed towards most pruriceptors being stimulated by pain as well as itch [1, 2]. One method of explaining this convergence is the expression of TRPV1 ion channels in pruriceptors. Although these are important for detecting itch, it is also expressed in nociceptors, and is stimulated by the classic pain stimulus found in peppers, capsaicin .
The relationship between itch and pain continues to the spinal cord. As mentioned, the spinothalamic tract (STT) is of special interest in understanding the distinction between itch and pain, as both sensations traverse the same pathway. Transecting the anterolateral funiculus where the tract ascends has eliminated sensitivity to itch, pain, and temperature, establishing the common usage of the tract by these sensations . Electrophysiological recordings of primate STT neurons when given different types of sensory stimuli also revealed that two thirds of the nociceptors were sensitive to itch stimuli as well as pain, again highlighting the apparent overlap between itch and pain in the spinal cord .
The relationship between itch and pain is best understood as antagonistic. Recordings of STT pruriceptive neurons showed that after being stimulated by histamine (itch/pruritic stimuli) the neuronal firing decreased when the skin was scratched. However, the same neuron increased firing after scratching in response to capsaicin. Although being activated by both pain and itch stimuli, the difference in response to scratching suggests an antagonistic relationship between pruriceptive and nociceptive neurons via inhibitory interneurons .
The intersection between pain and itch raises the question of the brain’s perception of pain and itch as distinct in the presence of much overlap. There are numerous theories and models attempting to explain the nature of this relationship, which will be overviewed in the following sections.
Classical Models of Itch and Pain Discrimination
Given observations on the overlaps between itch and pain, itch was first theorized to be a subset of pain in the intensity model. This postulates that polymodal neurons (sensitive to many modalities) differentiate between itch and pain through patterns of firing or “intensity” due to weak or strong stimulation [1, 4, 6, 10]. The model was tested by delivering electrical pulses to the skin that varied in frequency. Although the results seemingly disproved the theory as it only increased the intensity of itch felt, rather than transforming it to pain, the theory has not yet been discounted . Itch stimuli has been shown to trigger lower firing rates compared to painful stimuli in both peripheral and STT neurons, suggesting that firing rates do have some role in itch perception [6, 9]. Furthermore, both itch and pain stimuli give rise to “bursting” patterns of action potentials, and the interburst interval is shorter in response to capsaicin/pain. This suggests some level of temporal coding, when information is coded based on the timing of action potentials or intervals between them. This aligns with the intensity model as a polymodal neuron could code for itch and pain depending on the rate of action potentials or their intervals .
The intensity model’s basic principle lies in neurons activated by both pain and itch, and seemingly aligned with the previously mentioned research identifying pruriceptors as a subset of nociceptors and activated by both pain and itch. However, the discovery of itch-specific neurons further complicated the validity of the model, lending support to the labeled line model instead.
Labeled Line or Specificity Theory
Labeled line refers to the idea that there exists a specific, separate “line” or neural pathway devoted to the sensation of itch – the opposite of the intensity model’s polymodal neurons. As early as the 1800s, researchers discovered there are specific spots on the skin which are activated by different sensory modalities: coolness, heat, pain, etc., giving rise to the labeled line theory. Recent electrophysiological studies have supported this for different sensations through establishing the presence of sensory fibers and spinal relay neurons tuned to only one sensory modality .
The labeled line theory’s validity for itch was confirmed by the presence of itch specific neurons. GRPR3+ neurons in the spinal cord were identified that differed from STT neurons in that they carried purely itch information [3, 12]. This was evident as when these neurons were treated with a toxin, not only was there loss of itch behavior (scratching), there was no change in pain behavior (wiping) . The discovery of these itch specific neurons was emphasized by the consequent discovery of MrgprA3+ neurons in the dorsal horn which were itch specific as well; their deletion also resulted in loss of itch behavior only . Furthermore, the neurons gave rise to purely itch behavior regardless of the nature of the stimulus – precisely as predicted by the labeled line . These discoveries gave significant support to the labeled line theory, yet the presence of itch neurons activated by pain remained a dilemma.
Modified Models of Itch and Pain
The theories of intensity and labeled line represent the two ends of the spectrum in understanding pain signalling – the first depends on polymodal neurons, and the latter on itch specific neurons. The discovery of neurons that fall under both complicate their validity, and suggest that an accurate model should include neurons sensitive to both itch and pain while capable of differentiating between the two .
Spatial Contrast Model
Spatial models expand on the intensity model, and do not require itch and pain specific neurons. It proposes that itch is felt in “spatial contrast,” or when a small population of nociceptors are activated, and pain is felt when a larger population is activated due to a stronger stimulus [6,10]. In a study, it was observed that a spicule (small pointed end) of both histamine (itch stimuli) and capsaicin resulted in itch sensation, yet an injection of only capsaicin resulted in pain activation . This could be explained by the spatial contrast theory in that the spicule activated a small number of nociceptors, resulting in itch, whereas the more widespread injection stimulated a larger number of nociceptors, resulting in pain.
According to the model, a small number of even non-pruriceptive nociceptors activated should result in itch, eliminating the need for a labeled line. However, there remains an obstacle in this model as well – there was no decrease of itch sensation relative to pain when the area of exposure to stimuli increased, although the model predicts this should in theory activate a greater number of receptors [6, 13].
Selectivity Theory and Population Coding
The population coding theory – also known as the selectivity theory – modifies the labeled line, proposing that although there are specific sensory labeled lines, the antagonistic interaction between them shapes perception of itch. It takes into account the overlap between nociceptors and pruriceptors as well as pain’s inhibition of itch, proposing that pruriceptors are a smaller subset of nociceptors and are linked to them by inhibitory interneurons [1,11]. Theoretically, activation of the larger nociceptive population – including pruriceptors – is felt as pain, as the activation of the pain neurons “masks” the sensation of itch. Yet if only the smaller itch specific subset is activated, this is felt as purely itch, as there is no activation, and consequently no inhibition from the nociceptive neurons [1, 11, 14].
There have been numerous studies that appear to support this hypothesis. In one, the vesicular glutamate transporter VGLUT2 was deleted from DRG nociceptive neurons, affecting their ability to signal. This resulted in spontaneous itch in mice along with a decrease in pain behavior and, importantly, itch behavior resulting from capsaicin injections . These results were paralleled in another study where blocking pruriceptors had no effect on pain, yet deleting TRPV1 in a group of nociceptive neurons led to capsaicin to be perceived as itch . These two studies suggest groups of nociceptors are involved in inhibiting and masking itch, as deleting their receptors results in itch signaling instead, supporting the population coding theory.
It is also necessary to identify an inhibitory neuron to explain the antagonistic relationship between the nociceptors and pruriceptors; Bhlhb5 neurons are one such interneuron. When Bhlhb5 was knocked out in mice, there was increased itch behavior that ultimately resulted in lesions from itching and licking . This suggests that the interneuron, and perhaps other interneurons as well, are responsible for inhibiting and regulating itch, further bolstering the support for the population coding model.
Gate Control and Leaky Gate Model
The gate control theory hypothesizes that nociceptive transmission neurons in the spinal cord receive input from both nociceptive primary neurons, and Aβ fibers: primary neurons attuned to non-nociceptive stimuli such as touch. These Aβ fibers in turn inhibit the nociceptive neurons via interneurons, effectively creating a “gate” that can halt transmission of pain or itch . The previously mentioned Bhlhb+ interneurons support this gate control model as well [10, 16].
This model was recently further refined into the “leaky gate” theory. This builds on the intensity theory and modifies the gate control theory by substituting Grp+ neurons in the role of Aβ fibers. Grp+ spinal cord neurons receive strong input from pain sensory neurons and weak input from itch specific neurons, coding for itch in an intensity dependent manner and inhibiting pain. This model is different from gate control in that it lets weak pain signals “leak” through while suppressing strong pain signals to prevent an overwhelming pain sensation. When strongly activated by pain, these interneurons inhibit pain, whereas due to weak activation from itch, it does not inhibit pain . This model is able to explain the phenomenon that itch is often accompanied with a prickly, burning pain: it proposes that itch is not strong enough to inhibit pain sensation, resulting in a weak pain sensation accompanying itch .
A few of the major theories of itch perception have been discussed in an attempt to illuminate how itch is attenuated by the presence of pain in an inverse relationship. The intensity theory and the labeled line theory are both supported by the presence of polymodal neurons and itch specific neurons, respectively. However, given their opposing views, the accuracy of both theories is undermined by support for the other; this indicates the need for a model that is able to reconcile itch specificity with neurons attuned to both itch and pain.
The following models attempted to ease the apparent discord between the two previous models. The spatial model expands on the intensity model while providing a possible mechanism by which pain and itch could be felt from the same population of neurons. On the other hand, the population coding model expands on itch specific neurons of the labeled line while accommodating the inverse relationship between itch and pain. Lastly, the leaky gate model combines aspects of both intensity and selectivity theories.
These theories attempt to explain itch and pain crosstalk; the importance of understanding this relationship is seen in both acute and chronic itch pathophysiology in cases of crosstalk dysfunction. The previously discussed Bhlhb+ neurons are a prime example of the consequences of impaired itch and pain interaction [2, 16]. Research has shown that knocking out these interneurons – thereby severing the connection between itch and pain – results in chronic itch-like behavior such as lesions from scratching . This suggests that chronic itch may result from uninhibited, unregulated itch when pain is no longer permitted to suppress itch [2, 16].
This example highlights the importance of the application of the interaction between pain and itch. Not only does understanding the intersection between the two sensations provide a better understanding of itch mechanisms, the very intersection itself has an important role in itch pathophysiology, of which there is much that is still unknown. With the advent of new discoveries of new aspects of the itch pathway, these current models will continue to develop.
- Patel KN, Dong X. 2010. An Itch To Be Scratched. Neuron. 68(3):334-339. doi: 10.1016/j.neuron.2010.10.018.
- Liu T, Ji RR. 2013. New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms?. Pflugers Arch. 465(12):1671-1685. doi:10.1007/s00424-013-1284-2
- Barry DM, Munanairi A, Chen ZF. 2018. Spinal Mechanisms of Itch Transmission. Neurosci Bull. 34(1):156-164. doi:10.1007/s12264-017-0125-2
- Dong X, Dong X. 2018. Peripheral and Central Mechanisms of Itch. Neuron. 98 (3):482-494, doi: 10.1016/j.neuron.2018.03.023.
- Lay M, Xinzhong D. Neural Mechanisms of Itch. Annual Review of Neuroscience, 43:187-205. doi: 10.1146/annurev-neuro-083019-024537
- LaMotte RH, Dong X, Ringkamp M. 2014. Sensory neurons and circuits mediating itch. Nat Rev Neurosci. 15(1):19-31. doi: 10.1038/nrn3641
- Han L, Ma C, Liu Q, Weng H, Cui Y, Tang Z, Hao-Jui Weng, Yiyuan Cui, Zongxiang Tang, Yushin Kim, Hong Nie, Lintao Qu, Kush N Patel, Zhe Li, Benjamin McNeil, Shaoqiu He, Yun Guan, Bo Xiao, Robert H LaMotte & Xinzhong Dong .2013. A subpopulation of nociceptors specifically linked to itch. Nat Neurosci 16, 174–182. doi: 10.1038/nn.3289
- Carstens E, Iodi MC, Akiyama T, Davoodi A, Nagamine M. 2018. Opposing effects of cervical spinal cold block on spinal itch and pain transmission, Itch. 3(3):16 doi: 10.1097/itx.0000000000000016
- Davidson S, Zhang X, Khasabov SG, Moser HR, Honda CN, Simone DA, Giesler GJ Jr. 2012. Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate. J Neurophysiol. 108(6):1711-23. doi: 10.1152/jn.00206.2012.
- Sun S, Xu Q, Guo C, Guan Y, Liu Q, Dong X. 2017. Leaky Gate Model: Intensity-Dependent Coding of Pain and Itch in the Spinal Cord. Neuron. 93(4):840-853.e5. doi:10.1016/j.neuron.2017.01.012
- Ma Q. 2010. Labeled lines meet and talk: population coding of somatic sensations. J Clin Invest. 120(11):3773-3778. doi:10.1172/JCI43426
- Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF. 2009. Cellular basis of itch sensation. Science. 325(5947):1531-1534. doi:10.1126/science.1174868
- Sikand P, Shimada SG, Green BG, LaMotte RH. 2009. Similar itch and nociceptive sensations evoked by punctate cutaneous application of capsaicin, histamine and cowhage. Pain, 144(1-2), 66–75. https://doi.org/10.1016/j.pain.2009.03.001
- Liu Y, Abdel Samad O, Zhang L, Duan B, Tong Q, Lopes C, Ji RR, Lowell BB, Ma Q. 2010. VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch. Neuron, 68(3), 543–556. https://doi.org/10.1016/j.neuron.2010.09.008
- Roberson DP, Gudes S, Sprague JM, Patoski HA, Robson VK, Blasl F, Duan B, Oh SB, Bean BP, Ma Q, Binshtok AM, Woolf CJ. 2013. Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons. Nature neuroscience 16(7):910-8. doi: 10.1038/nn.3404.
- Ross SE, Mardinly AR, McCord, AE, Zurawski J, Cohen S, Jung C, Hu L, Mok SI, Shah A, Savner EM, Tolias C, Corfas R, Chen S, Inquimbert P, Xu Y, McInnes RR, Rice FL, Corfas G, Ma Q, Woolf CJ, Greenberg ME. 2010. Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron, 65(6), 886–898. https://doi.org/10.1016/j.neuron.2010.02.025