- Email: [email protected]
A Spinal Circuit for Mechanically-Evoked Itch
TINS 1194 No. of Pages 2
Spotlight
A Spinal Circuit for Mechanically-Evoked Itch 1, ,@
Steve Davidson *
A satisfactory neurobiological understanding of itch has proved difficult to reach. Bourane et al. have now uncovered a previously unrecognized spinal circuit for mechanically-induced itch and elucidated a mechanism that keeps it in check. Dysregulation of this circuit could contribute to chronic itch, suggesting a new strategy for itch relief. Unrelenting itch was punishment for those ancients cast into the penultimate circle of Dante's Inferno. Sadly, the currently available treatments for chronic pruritus leave many present-day patients with little greater hope for salvation. However, recent advances have identified multiple, distinct neural pathways for itch, buoying optimism for the future development of new classes of anti-pruritics. Histamine, proteases, and other pruritic chemicals released from skin cells or exogenous sources, act on receptors localized to the distal endings of a subset of primary afferent nociceptors to produce a sensation of itch. Antihistamines often work well to treat itch from urticaria (hives) and allergy, but are far less effective for the chronic pruritus associated with atopic dermatitis, psoriasis, renal dysfunction, HIV, and other systemic diseases. The identification of non-histaminergic pathways for itch, first using cowhage and then through the activation of myriad histamine-independent, ligand-gated receptors, seemed to explain much of the poor efficacy of antihistamines [1–3]. Non-chemically evoked itch, such as that mediated by mechanical stimulation from a wool sweater, a crawling insect, or a
droplet of sweat trickling down the skin, was assumed to result from activation of mechano-sensitive, pruritogen-sensitive nociceptors (i.e., pruriceptors). Experimental evidence that itch can in fact be elicited independent of nociceptor activation came from a recent human psychophysics study in which mechanical stimulation of fine vellus hair produced a robust desire to scratch [4]. Bourane and colleagues have now identified a crucial piece of the neural circuit responsible for mechanically-induced itch by ablating or silencing a select population of spinal dorsal horn neurons in mice that at [7_TD$IF]some time expressed neuropeptide Y (NPY*) [5]. Loss of these NPY* spinal neurons produced excessive scratching when the animal was gently poked with a mechanical probe and eventually led to a persistent scratching phenotype. Interestingly, this scratching behavior was independent of itch produced by pruritic chemicals, suggesting the NPY* neurons contributed to a distinct pathway selective for mechanically-evoked itch. Further investigation revealed that the NPY* neurons expressed markers of inhibitory interneurons, indicating that the itch produced by loss of NPY* neurons was generated by disinhibition of a previously unrecognized itch pathway ([8_TD$IF]Figure 1). Whether clinically important pruritic conditions can be shown to result from dysregulation of this circuit is now an important question. Itch evokes the desire to scratch and scratching blocks the perception of itch. The site for inhibition of the itch signal by scratching was localized to a spinal inhibitory gate based on the observation that pruritogen-responsive spinothalamic tract neurons became inhibited after scratching the skin [6]. Subsequently, a class of spinal inhibitory neurons identified by transient expression of Bhlhb5 during development [9_TD$IF]was found to suppress itch; when these cells were ablated, scratching behavior was generated [7]. Bhlhb5 neurons express somatostatin, receive input from nociceptors, and release dynorphin,
a k-opioid receptor agonist, which acts to block scratching behavior [8] ([8_TD$IF]Figure 1). [10_TD$IF]By contrast, loss of the NPY* inhibitory interneurons did not lead to a loss in somatostatin or dynorphin expression in the dorsal horn, indicating that the NPY* neurons constitute a novel population of itch suppressing spinal inhibitory neurons, distinct from the Bhlhb5 subset [5]. Mechanically and chemically sensitive nociceptors innervate Bhlhb5 neurons, suggesting a mechanism by which scratching and other counter-stimuli inhibit itch. The innervation of Bhlhb5 neurons by pruriceptors or by low threshold mechanoreceptors (LTMs) has not been documented. [10_TD$IF]By contrast, LTMs appear to make direct contacts onto NPY* neurons [5], although the precise assemblage of mechanoreceptors, nociceptors, and pruriceptors that innervate NPY* neurons is not yet clear. Bourane et al. also report that large diameter, myelinated fibers supply direct functional input onto NPY* neurons, as do unidentified C- and Ad fibers, suggesting that NPY* interneurons are likely activated by various somatosensory stimuli and could contribute to the inhibition of itch by scratching and other counter-stimuli. Paradoxically, LTMs appear to both produce itch as well as activate the inhibitory interneurons that suppress itch. Is it possible that coordinated inhibitory input contributes to the coding of mechanical itch or tactile sensation? Pruriceptive spinal neurons respond with greater inter-spike intervals to pruritogens than to pain-producing stimuli, but it is uncertain whether discharge rate contributes to coding itch [1]. In addition to two itch-suppressing spinal interneurons, two excitatory spinal neurons critical for signaling itch have been identified. One expresses the gastrinreleasing peptide receptor (GRPR) and the other expresses the natriuretic polypeptide receptor subtype A (NPRA) [9,10]. Loss of either excitatory interneuron greatly reduces scratching behavior elicited by chemical and peptide mediators.
Trends in Neurosciences, Month Year, Vol. xx, No. yy
1
TINS 1194 No. of Pages 2
Mechanical Itch C Aδ LTM
columns and medial lemniscus, a pathway not presently known to encode itch.
Key: Inhibitory interneuron
NPY*
Excitatory interneuron Somatostan receptor Dynorphin vesicle
?
P
B5
GRPR
ITCH
Chemical Itch C Aδ LTM
The capacity to distinguish fine differences in potentially harmful stimuli has allowed the evolutionary development of divergent behaviors to protect the body, including: withdrawal, guarding, rubbing, flinching, and scratching. Our understanding of itch has only recently expanded, but evidence for multiple neural pathways converging to one perception (itch) which is best understood as a motivation for a specific behavior (scratching) indicates a unique complexity that will require research along the entire neuraxis to fully resolve. 1
Figure 1. Distinct [1_TD$IF]Pathways for [2_TD$IF]Mechanical and [3_TD$IF]Chemical [4_TD$IF]Itch. Schematic of spinal circuitry leading to mechanically-evoked or chemically-evoked itch. Inhibitory interneurons identified by one-time expression of NPY receive inputs from a wide range of peripheral afferent fibers of varying diameter, including low-threshold mechanoreceptors. Loss of NPY neurons produces disinhibition of an unidentified spinal excitatory neuron (?) leading to itch. Chemically evoked itch is gated by the Bhlhb5 (B5) inhibitory interneuron, which receives input from at least C nociceptors (unknown inputs shown in gray), and involves GRPR and NPRA (not shown) spinal excitatory interneurons. The molecular identities of spinal projection neurons (P) involved in itch are unknown.
However, in mice without NPY* inhibitory interneurons, elimination of GRPR neurons failed to abolish the induced alloknesis (touch evoked itch), indicating that mechanically elicited itch follows a pathway distinct from the GRPR neurons. Because NPRA spinal neurons are thought to be located presynaptic to GRPR neurons [10], it is likely that the mechano-itch circuit is likewise independent of NPRA neurons, although this requires direct verification. These observations open the possibility for an as yet unidentified itch-selective spinal excitatory interneuron or projection neuron. Indeed, Bourane et al. report that unidentified dorsal horn neurons exhibited enhanced
2
Trends in Neurosciences, Month Year, Vol. xx, No. yy
after-discharge to gentle stroking of the hairy skin after NPY* neurons were ablated [5]. Whether the mechanical and chemicalevoked itch pathways synapse onto the same ascending projection neurons or maintain independence is not known. Spinal projection neurons are classified as nociceptive specific (NS), wide dynamic range (WDR), or low threshold (LT) types, as determined by mechanical sensitivity. Many chemical pruritogen-responsive spinal neurons are NS type, but mechanical itch is likely instead to ascend via WDR or possibly LT type neurons [1,3]. Alternatively, LTMs can ascend via the dorsal
Pain Research Center, Department of Anesthesiology,
University of Cincinnati College of Medicine, Cincinnati, OH [5_TD$IF]45267, USA @ https://twitter.com/restinpotential *Correspondence: [email protected] (S. Davidson). http://dx.doi.org/10.1016/j.tins.2015.12.001 References 1. LaMotte, R.H. et al. (2014) Sensory neurons and circuits mediating itch. Nat. Rev. Neurosci. 15, 19–31 2. Bautista, D.M. et al. (2014) Why we scratch an itch: the molecules, cells and circuits of itch. Nat. Neurosci. 17, 175–182 3. Akiyama, T. and Carstens, E. (2014) Spinal coding of itch and pain. In Itch: Mechanisms and Treatment (Carstens, E. and Akiyama, T., eds), CRC Press 4. Fukuoka, M. et al. (2013) Mechanically evoked itch in humans. Pain 154, 897–904 5. Bourane, S. et al. (2015) Gate control of mechanical itch by a subpopulation of spinal cord interneurons. Science 350, 550–554 6. Davidson, S. et al. (2009) Relief of itch by scratching: statedependent inhibition of primate spinothalamic tract neurons. Nat. Neurosci. 12, 544–546 7. Ross, S.E. et al. (2010) Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 65, 886–898 8. Kardon, A.P. et al. (2014) Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82, 573–586 9. Sun, Y.G. et al. (2009) Cellular basis of itch sensation. Science 325, 1531–1534 10. Mishra, S.K. and Hoon, M.A. (2013) The cells and circuitry for itch responses in mice. Science 340, 968–971
Spotlight
A Spinal Circuit for Mechanically-Evoked Itch 1, ,@
Steve Davidson *
A satisfactory neurobiological understanding of itch has proved difficult to reach. Bourane et al. have now uncovered a previously unrecognized spinal circuit for mechanically-induced itch and elucidated a mechanism that keeps it in check. Dysregulation of this circuit could contribute to chronic itch, suggesting a new strategy for itch relief. Unrelenting itch was punishment for those ancients cast into the penultimate circle of Dante's Inferno. Sadly, the currently available treatments for chronic pruritus leave many present-day patients with little greater hope for salvation. However, recent advances have identified multiple, distinct neural pathways for itch, buoying optimism for the future development of new classes of anti-pruritics. Histamine, proteases, and other pruritic chemicals released from skin cells or exogenous sources, act on receptors localized to the distal endings of a subset of primary afferent nociceptors to produce a sensation of itch. Antihistamines often work well to treat itch from urticaria (hives) and allergy, but are far less effective for the chronic pruritus associated with atopic dermatitis, psoriasis, renal dysfunction, HIV, and other systemic diseases. The identification of non-histaminergic pathways for itch, first using cowhage and then through the activation of myriad histamine-independent, ligand-gated receptors, seemed to explain much of the poor efficacy of antihistamines [1–3]. Non-chemically evoked itch, such as that mediated by mechanical stimulation from a wool sweater, a crawling insect, or a
droplet of sweat trickling down the skin, was assumed to result from activation of mechano-sensitive, pruritogen-sensitive nociceptors (i.e., pruriceptors). Experimental evidence that itch can in fact be elicited independent of nociceptor activation came from a recent human psychophysics study in which mechanical stimulation of fine vellus hair produced a robust desire to scratch [4]. Bourane and colleagues have now identified a crucial piece of the neural circuit responsible for mechanically-induced itch by ablating or silencing a select population of spinal dorsal horn neurons in mice that at [7_TD$IF]some time expressed neuropeptide Y (NPY*) [5]. Loss of these NPY* spinal neurons produced excessive scratching when the animal was gently poked with a mechanical probe and eventually led to a persistent scratching phenotype. Interestingly, this scratching behavior was independent of itch produced by pruritic chemicals, suggesting the NPY* neurons contributed to a distinct pathway selective for mechanically-evoked itch. Further investigation revealed that the NPY* neurons expressed markers of inhibitory interneurons, indicating that the itch produced by loss of NPY* neurons was generated by disinhibition of a previously unrecognized itch pathway ([8_TD$IF]Figure 1). Whether clinically important pruritic conditions can be shown to result from dysregulation of this circuit is now an important question. Itch evokes the desire to scratch and scratching blocks the perception of itch. The site for inhibition of the itch signal by scratching was localized to a spinal inhibitory gate based on the observation that pruritogen-responsive spinothalamic tract neurons became inhibited after scratching the skin [6]. Subsequently, a class of spinal inhibitory neurons identified by transient expression of Bhlhb5 during development [9_TD$IF]was found to suppress itch; when these cells were ablated, scratching behavior was generated [7]. Bhlhb5 neurons express somatostatin, receive input from nociceptors, and release dynorphin,
a k-opioid receptor agonist, which acts to block scratching behavior [8] ([8_TD$IF]Figure 1). [10_TD$IF]By contrast, loss of the NPY* inhibitory interneurons did not lead to a loss in somatostatin or dynorphin expression in the dorsal horn, indicating that the NPY* neurons constitute a novel population of itch suppressing spinal inhibitory neurons, distinct from the Bhlhb5 subset [5]. Mechanically and chemically sensitive nociceptors innervate Bhlhb5 neurons, suggesting a mechanism by which scratching and other counter-stimuli inhibit itch. The innervation of Bhlhb5 neurons by pruriceptors or by low threshold mechanoreceptors (LTMs) has not been documented. [10_TD$IF]By contrast, LTMs appear to make direct contacts onto NPY* neurons [5], although the precise assemblage of mechanoreceptors, nociceptors, and pruriceptors that innervate NPY* neurons is not yet clear. Bourane et al. also report that large diameter, myelinated fibers supply direct functional input onto NPY* neurons, as do unidentified C- and Ad fibers, suggesting that NPY* interneurons are likely activated by various somatosensory stimuli and could contribute to the inhibition of itch by scratching and other counter-stimuli. Paradoxically, LTMs appear to both produce itch as well as activate the inhibitory interneurons that suppress itch. Is it possible that coordinated inhibitory input contributes to the coding of mechanical itch or tactile sensation? Pruriceptive spinal neurons respond with greater inter-spike intervals to pruritogens than to pain-producing stimuli, but it is uncertain whether discharge rate contributes to coding itch [1]. In addition to two itch-suppressing spinal interneurons, two excitatory spinal neurons critical for signaling itch have been identified. One expresses the gastrinreleasing peptide receptor (GRPR) and the other expresses the natriuretic polypeptide receptor subtype A (NPRA) [9,10]. Loss of either excitatory interneuron greatly reduces scratching behavior elicited by chemical and peptide mediators.
Trends in Neurosciences, Month Year, Vol. xx, No. yy
1
TINS 1194 No. of Pages 2
Mechanical Itch C Aδ LTM
columns and medial lemniscus, a pathway not presently known to encode itch.
Key: Inhibitory interneuron
NPY*
Excitatory interneuron Somatostan receptor Dynorphin vesicle
?
P
B5
GRPR
ITCH
Chemical Itch C Aδ LTM
The capacity to distinguish fine differences in potentially harmful stimuli has allowed the evolutionary development of divergent behaviors to protect the body, including: withdrawal, guarding, rubbing, flinching, and scratching. Our understanding of itch has only recently expanded, but evidence for multiple neural pathways converging to one perception (itch) which is best understood as a motivation for a specific behavior (scratching) indicates a unique complexity that will require research along the entire neuraxis to fully resolve. 1
Figure 1. Distinct [1_TD$IF]Pathways for [2_TD$IF]Mechanical and [3_TD$IF]Chemical [4_TD$IF]Itch. Schematic of spinal circuitry leading to mechanically-evoked or chemically-evoked itch. Inhibitory interneurons identified by one-time expression of NPY receive inputs from a wide range of peripheral afferent fibers of varying diameter, including low-threshold mechanoreceptors. Loss of NPY neurons produces disinhibition of an unidentified spinal excitatory neuron (?) leading to itch. Chemically evoked itch is gated by the Bhlhb5 (B5) inhibitory interneuron, which receives input from at least C nociceptors (unknown inputs shown in gray), and involves GRPR and NPRA (not shown) spinal excitatory interneurons. The molecular identities of spinal projection neurons (P) involved in itch are unknown.
However, in mice without NPY* inhibitory interneurons, elimination of GRPR neurons failed to abolish the induced alloknesis (touch evoked itch), indicating that mechanically elicited itch follows a pathway distinct from the GRPR neurons. Because NPRA spinal neurons are thought to be located presynaptic to GRPR neurons [10], it is likely that the mechano-itch circuit is likewise independent of NPRA neurons, although this requires direct verification. These observations open the possibility for an as yet unidentified itch-selective spinal excitatory interneuron or projection neuron. Indeed, Bourane et al. report that unidentified dorsal horn neurons exhibited enhanced
2
Trends in Neurosciences, Month Year, Vol. xx, No. yy
after-discharge to gentle stroking of the hairy skin after NPY* neurons were ablated [5]. Whether the mechanical and chemicalevoked itch pathways synapse onto the same ascending projection neurons or maintain independence is not known. Spinal projection neurons are classified as nociceptive specific (NS), wide dynamic range (WDR), or low threshold (LT) types, as determined by mechanical sensitivity. Many chemical pruritogen-responsive spinal neurons are NS type, but mechanical itch is likely instead to ascend via WDR or possibly LT type neurons [1,3]. Alternatively, LTMs can ascend via the dorsal
Pain Research Center, Department of Anesthesiology,
University of Cincinnati College of Medicine, Cincinnati, OH [5_TD$IF]45267, USA @ https://twitter.com/restinpotential *Correspondence: [email protected] (S. Davidson). http://dx.doi.org/10.1016/j.tins.2015.12.001 References 1. LaMotte, R.H. et al. (2014) Sensory neurons and circuits mediating itch. Nat. Rev. Neurosci. 15, 19–31 2. Bautista, D.M. et al. (2014) Why we scratch an itch: the molecules, cells and circuits of itch. Nat. Neurosci. 17, 175–182 3. Akiyama, T. and Carstens, E. (2014) Spinal coding of itch and pain. In Itch: Mechanisms and Treatment (Carstens, E. and Akiyama, T., eds), CRC Press 4. Fukuoka, M. et al. (2013) Mechanically evoked itch in humans. Pain 154, 897–904 5. Bourane, S. et al. (2015) Gate control of mechanical itch by a subpopulation of spinal cord interneurons. Science 350, 550–554 6. Davidson, S. et al. (2009) Relief of itch by scratching: statedependent inhibition of primate spinothalamic tract neurons. Nat. Neurosci. 12, 544–546 7. Ross, S.E. et al. (2010) Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 65, 886–898 8. Kardon, A.P. et al. (2014) Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82, 573–586 9. Sun, Y.G. et al. (2009) Cellular basis of itch sensation. Science 325, 1531–1534 10. Mishra, S.K. and Hoon, M.A. (2013) The cells and circuitry for itch responses in mice. Science 340, 968–971