- Email: [email protected]
Bursting Enables GRP Neurons to Engage Spinal Itch Circuits
Neuron
Previews expands our understanding of goaldirected learning mechanisms. REFERENCES Albin, R.L., Young, A.B., and Penney, J.B. (1989). The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366–375. Brown, M.T., Tan, K.R., O’Connor, E.C., €scher, C. (2012). Nikonenko, I., Muller, D., and Lu Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning. Nature 492, 452–456. Gritton, H.J., Howe, W.M., Romano, M.F., DiFeliceantonio, A.G., Kramer, M.A., Saligrama, V., Bucklin, M.E., Zemel, D., and Han, X. (2019). Unique contributions of parvalbumin and cholin-
ergic interneurons in organizing striatal networks during movement. Nat. Neurosci. 22, 586–597. Holly, E.N., Davatolhagh, M.F., Choi, K., Alabi, O.O., Vargas Cifuentes, L., and Fuccillo, M.V. (2019). Striatal low-threshold spiking interneurons regulate goal-directed learning. Neuron 103, this issue, 92–101.
Owen, S.F., Berke, J.D., and Kreitzer, A.C. (2018). Fast-spiking interneurons supply feedforward control of bursting, calcium, and plasticity for efficient learning. Cell 172, 683–695.e615. Straub, C., Saulnier, J.L., Be`gue, A., Feng, D.D., Huang, K.W., and Sabatini, B.L. (2016). Principles of synaptic organization of GABAergic interneurons in the striatum. Neuron 92, 84–92.
Lee, K., Holley, S.M., Shobe, J.L., Chong, N.C., Cepeda, C., Levine, M.S., and Masmanidis, S.C. (2017). Parvalbumin interneurons modulate striatal output and enhance performance during associative learning. Neuron 93, 1451–1463.e4.
Tecuapetla, F., Jin, X., Lima, S.Q., and Costa, R.M. (2016). Complementary contributions of striatal projection pathways to action initiation and execution. Cell 166, 703–715.
O’Hare, J.K., Li, H., Kim, N., Gaidis, E., Ade, K., Beck, J., Yin, H., and Calakos, N. (2017). Striatal fast-spiking interneurons selectively modulate circuit output and are required for habitual behavior. eLife 6, 6.
Tepper, J.M., Koo´s, T., Ibanez-Sandoval, O., Tecuapetla, F., Faust, T.W., and Assous, M. (2018). Heterogeneity and diversity of striatal GABAergic interneurons: update 2018. Front. Neuroanat. 12, 91.
Bursting Enables GRP Neurons to Engage Spinal Itch Circuits Hugues Petitjean,1,2 Philippe Se´gue´la,2,3 and Reza Sharif-Naeini1,2,* 1Department
of Physiology and Cell Information Systems, McGill University, Montreal, QC, Canada Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada 3Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2019.06.009 2The
In this issue of Neuron, Pagani et al. (2019) find that itch signaling occurs only when GRP neurons fire action potentials in bursts. This enables GRP release and the activation of GRPR neurons, which help carry the itch signal to the brain. Itch is an evolutionary-conserved sense that protects us from potentially harmful stimuli such as mosquito bites and parasites. Based on the conservation of itch receptors in various species, this somatosensation appeared at least some 400 million years ago, when tetrapods first emerged (Mack and Kim, 2018). However, when itch becomes chronic, defined as lasting more than 6 weeks, it becomes highly debilitating and is associated with a decrease in the quality of life (Mack and Kim, 2018). This pathology underlies many skin disorders such as atopic dermatitis and psoriasis as well as chronic kidney and liver diseases. The unsuccessful management of chronic itch in these conditions stems from our limited insight into its underlying mechanisms. Therefore, despite recent advances in our un-
derstanding of molecules and neuronal pathways involved in the transmission of itch (Dong et al., 2001; Huang et al., 2018; Kardon et al., 2014), developments in this field remain desperately needed. Itch-producing compounds (pruritogens) activate their receptors on peripheral sensory neurons (pruriceptors), which send their central axons in the superficial layers of the dorsal horn of the spinal cord. A subset of these pruriceptors, expressing the receptor for the anti-malarial drug chloroquine MrgprA3 (Han et al., 2013), forms synaptic connections with excitatory interneurons that contain the neuropeptide gastrin-releasing peptide (GRP) (Albisetti et al., 2019). Activation of GRP neurons by primary afferents causes the release of the neuropeptide, along with glutamate, on a second subset of
excitatory interneurons, which express the GRP receptor (GRPR). Ablation of GRP neurons (Sun et al., 2017) or GRPR neurons (Sun et al., 2009) gives rise to mice with reduced responses to the injection of pruritogens, highlighting the essential role of this peptide/receptor pathway. However, the exact mode of communication between GRP and GRPR neurons in the context of itch signaling remained poorly understood. Particularly, given that GRP neurons are glutamatergic (Sun et al., 2017), it is unclear why deleting the GRPR can block itch behavior. Presumably, the release of GRP and its binding to GRPR acts in concert to the activation of postsynaptic glutamate receptors. In this issue of Neuron, the Zeilhofer group uses an elegant series of experimental approaches
Neuron 103, July 3, 2019 ª 2019 Elsevier Inc. 5
Neuron
Previews
Figure 1. Schematic Diagram Depicting How Pruritogens Can Elicit the Sensation of Itch Pruritogens activate their receptors in the peripheral terminals of pruriceptors located in the skin (the example of the MrgprA3-expressing pruriceptors is given here), which excites the sensory neuron and induces glutamate release at its central terminal in lamina II of the dorsal horn. This direct excitation of GRP-expressing neurons triggers a bursting behavior in these cells. The release of GRP from these neurons onto GRPR-expressing interneurons only occurs when GRP neurons burst, as opposed to single isolated action potentials. The binding of GRP to its receptor GRPR causes the inhibition of an inward rectifier potassium channel (Kir) that depolarizes the membrane voltage and brings it near the action potential threshold. When glutamate-elicited excitatory postsynaptic potentials (EPSPs) are superimposed on this depolarization, they reach the action potential threshold and the GRPR can then activate its downstream target, ultimately activating spinal projection neurons that carry the itch signal to supraspinal center.
to reveal the properties of the GRP-GRPR neuron synapse (Pagani et al., 2019). To examine the synaptic communication between these two subsets of neurons, they generated a triple transgenic mouse that expressed channelrhodopsin2-eYFP (ChR2-eYFP) fusion protein in GRP neurons and eGFP in GRPR neurons, allowing them to record from GRPR neurons while optogenetically stimulating GRP neurons and to confirm the monosynaptic nature of this communication. Interestingly, when postsynaptic responses of GRPR neuron were examined in response to single light pulse stimulation of GRP neurons, none of the excitatory GRPR neurons were able to generate action potentials. The excitation produced by such stimulation was restricted to subthreshold depolarizations, leading Pagani et al. (2019) to question whether such activation modality truly reflects the activity of GRP neurons activated by peripheral pruriceptors. They thus generated another triple transgenic mouse line in which MrgprA3expressing pruriceptors expressed ChR2 and GRP neurons expressed eGFP. This enabled them to record, in spinal cord slice preparations, from GRP neurons 6 Neuron 103, July 3, 2019
while stimulating the central terminals of the primary pruriceptors. Surprisingly, their current-clamp recordings indicated that a single (4 ms) light pulse stimulation of MrgprA3 fibers triggered bursts of 2–5 action potentials in GRP neurons. This observation prompted them to determine whether burst-like firing in GRP neurons would be more appropriate when communicating with downstream GRPR neurons. They therefore mimicked this firing pattern in their subsequent experiments on synaptic communication between GRP and GRPR neurons. Through the use of temporally patterned optogenetic light stimulation, they tested whether burst-like stimulation of GRP neurons would produce action potentials in GRPR neurons. Surprisingly, this led to the gradual depolarization of GRPR neurons followed by the generation of action potentials. Furthermore, the depolarization and spontaneous activity that were generated persisted for minutes after the synaptic stimulation had stopped. To examine whether the gradual depolarization and excitation produced by burst-like activity in GRP neurons was due to GRP release or to glutamate receptor-dependent plasticity, they repeated
the experiments in the presence of GRPR or AMPA/NMDA receptor antagonists, respectively. The progressive depolarization and excitation persisted in the presence of glutamate receptor antagonists but were almost completely abolished by GRPR antagonists, thus highlighting the critical role of peptidergic signaling at this synapse. The metabotropic signaling pathway engaged by GRP was examined by exogenous application of the peptide and indicated that the depolarization was associated with an increase in input resistance, suggesting that some background potassium channels had closed. Through a series of pharmacological and electrophysiological approaches, these channels were identified as Kir-like and Kv4.2-like potassium channels (Figure 1). From these findings, Pagani et al. (2019) predicted that burst-like activity in GRP neurons was necessary to elicit GRP release, which would produce spiking in excitatory GRPR neurons and lead to the activation of spinal relays of pruriceptive information. To test this prediction in vivo, they chronically implanted GRP-ChR2 mice with fiber optics directed toward the dorsal horn and stimulated GRP neurons with brief pulses of light, applied either as a single stimulus or as a burst. Their results indicated that only during burst-like stimulation of GRP neurons was an aversive reaction elicited in the animals. This effect occurred with a certain delay and outlasted the stimulation period by several minutes, in agreement with the different time courses of pain and itch responses. The past decade has seen important advances in our understanding of how itch is perceived at the molecular level and how it is transmitted to the nervous system at the circuit level. A more challenging task has been to understand how these mechanisms differ from those involved in pain transmission in their necessity for peptidergic transmission. This involves a careful examination of the synaptic physiology of these synapses. Through a ‘‘tour de force’’ approach involving the generation of triple transgenic mice, in vivo optogenetic modulation of itch pathways and slice electrophysiology, the Zeilhofer lab identified a mechanism that explains how the synaptic transmission of itch signals differs
Neuron
Previews from pain signals. Future research may explain how this intracellular cascade can interact with others activated in GRPR neurons. For instance, it was recently demonstrated that these neurons also express the kappa-opioid receptor (KOR), whose activation can desensitize GRPR (Munanairi et al., 2018). Finally, the findings of the Zeilhofer lab open interesting avenues for integrating the unique role of the synapse between spinal GRP and GRPR neurons in the pathophysiology of chronic itch. REFERENCES Albisetti, G.W., Pagani, M., Platonova, E., Ho¨sli, L., Johannssen, H.C., Fritschy, J.M., Wildner, H., and Zeilhofer, H.U. (2019). Dorsal horn gastrinreleasing peptide expressing neurons transmit
spinal itch but not pain signals. J. Neurosci. 39, 2238–2250. Dong, X., Han, S., Zylka, M.J., Simon, M.I., and Anderson, D.J. (2001). A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106, 619–632. Han, L., Ma, C., Liu, Q., Weng, H.J., Cui, Y., Tang, Z., Kim, Y., Nie, H., Qu, L., Patel, K.N., et al. (2013). A subpopulation of nociceptors specifically linked to itch. Nat. Neurosci. 16, 174–182. Huang, J., Polga´r, E., Solinski, H.J., Mishra, S.K., Tseng, P.Y., Iwagaki, N., Boyle, K.A., Dickie, A.C., Kriegbaum, M.C., Wildner, H., et al. (2018). Circuit dissection of the role of somatostatin in itch and pain. Nat. Neurosci. 21, 707–716. Kardon, A.P., Polga´r, E., Hachisuka, J., Snyder, L.M., Cameron, D., Savage, S., Cai, X., Karnup, S., Fan, C.R., Hemenway, G.M., et al. (2014). Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82, 573–586.
Mack, M.R., and Kim, B.S. (2018). The itch-scratch cycle: a neuroimmune perspective. Trends Immunol. 39, 980–991. Munanairi, A., Liu, X.Y., Barry, D.M., Yang, Q., Yin, J.B., Jin, H., Li, H., Meng, Q.T., Peng, J.H., Wu, Z.Y., et al. (2018). Non-canonical opioid signaling inhibits itch transmission in the spinal cord of nice. Cell Rep. 23, 866–877. Pagani, M., Albisetti, G.W., Sivakumar, N., Wildner, H., Santello, M., Johannssen, H.C., and Zeilhofer, H.U. (2019). How gastrin-releasing peptide opens the spinal gate for itch. Neuron 103, this issue, 102–117. Sun, Y.G., Zhao, Z.Q., Meng, X.L., Yin, J., Liu, X.Y., and Chen, Z.F. (2009). Cellular basis of itch sensation. Science 325, 1531–1534. Sun, S., Xu, Q., Guo, C., Guan, Y., Liu, Q., and Dong, X. (2017). Leaky gate model: intensitydependent coding of pain and itch in the spinal cord. Neuron 93, 840–853.e5.
Neuron 103, July 3, 2019 7
Previews expands our understanding of goaldirected learning mechanisms. REFERENCES Albin, R.L., Young, A.B., and Penney, J.B. (1989). The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366–375. Brown, M.T., Tan, K.R., O’Connor, E.C., €scher, C. (2012). Nikonenko, I., Muller, D., and Lu Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning. Nature 492, 452–456. Gritton, H.J., Howe, W.M., Romano, M.F., DiFeliceantonio, A.G., Kramer, M.A., Saligrama, V., Bucklin, M.E., Zemel, D., and Han, X. (2019). Unique contributions of parvalbumin and cholin-
ergic interneurons in organizing striatal networks during movement. Nat. Neurosci. 22, 586–597. Holly, E.N., Davatolhagh, M.F., Choi, K., Alabi, O.O., Vargas Cifuentes, L., and Fuccillo, M.V. (2019). Striatal low-threshold spiking interneurons regulate goal-directed learning. Neuron 103, this issue, 92–101.
Owen, S.F., Berke, J.D., and Kreitzer, A.C. (2018). Fast-spiking interneurons supply feedforward control of bursting, calcium, and plasticity for efficient learning. Cell 172, 683–695.e615. Straub, C., Saulnier, J.L., Be`gue, A., Feng, D.D., Huang, K.W., and Sabatini, B.L. (2016). Principles of synaptic organization of GABAergic interneurons in the striatum. Neuron 92, 84–92.
Lee, K., Holley, S.M., Shobe, J.L., Chong, N.C., Cepeda, C., Levine, M.S., and Masmanidis, S.C. (2017). Parvalbumin interneurons modulate striatal output and enhance performance during associative learning. Neuron 93, 1451–1463.e4.
Tecuapetla, F., Jin, X., Lima, S.Q., and Costa, R.M. (2016). Complementary contributions of striatal projection pathways to action initiation and execution. Cell 166, 703–715.
O’Hare, J.K., Li, H., Kim, N., Gaidis, E., Ade, K., Beck, J., Yin, H., and Calakos, N. (2017). Striatal fast-spiking interneurons selectively modulate circuit output and are required for habitual behavior. eLife 6, 6.
Tepper, J.M., Koo´s, T., Ibanez-Sandoval, O., Tecuapetla, F., Faust, T.W., and Assous, M. (2018). Heterogeneity and diversity of striatal GABAergic interneurons: update 2018. Front. Neuroanat. 12, 91.
Bursting Enables GRP Neurons to Engage Spinal Itch Circuits Hugues Petitjean,1,2 Philippe Se´gue´la,2,3 and Reza Sharif-Naeini1,2,* 1Department
of Physiology and Cell Information Systems, McGill University, Montreal, QC, Canada Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada 3Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2019.06.009 2The
In this issue of Neuron, Pagani et al. (2019) find that itch signaling occurs only when GRP neurons fire action potentials in bursts. This enables GRP release and the activation of GRPR neurons, which help carry the itch signal to the brain. Itch is an evolutionary-conserved sense that protects us from potentially harmful stimuli such as mosquito bites and parasites. Based on the conservation of itch receptors in various species, this somatosensation appeared at least some 400 million years ago, when tetrapods first emerged (Mack and Kim, 2018). However, when itch becomes chronic, defined as lasting more than 6 weeks, it becomes highly debilitating and is associated with a decrease in the quality of life (Mack and Kim, 2018). This pathology underlies many skin disorders such as atopic dermatitis and psoriasis as well as chronic kidney and liver diseases. The unsuccessful management of chronic itch in these conditions stems from our limited insight into its underlying mechanisms. Therefore, despite recent advances in our un-
derstanding of molecules and neuronal pathways involved in the transmission of itch (Dong et al., 2001; Huang et al., 2018; Kardon et al., 2014), developments in this field remain desperately needed. Itch-producing compounds (pruritogens) activate their receptors on peripheral sensory neurons (pruriceptors), which send their central axons in the superficial layers of the dorsal horn of the spinal cord. A subset of these pruriceptors, expressing the receptor for the anti-malarial drug chloroquine MrgprA3 (Han et al., 2013), forms synaptic connections with excitatory interneurons that contain the neuropeptide gastrin-releasing peptide (GRP) (Albisetti et al., 2019). Activation of GRP neurons by primary afferents causes the release of the neuropeptide, along with glutamate, on a second subset of
excitatory interneurons, which express the GRP receptor (GRPR). Ablation of GRP neurons (Sun et al., 2017) or GRPR neurons (Sun et al., 2009) gives rise to mice with reduced responses to the injection of pruritogens, highlighting the essential role of this peptide/receptor pathway. However, the exact mode of communication between GRP and GRPR neurons in the context of itch signaling remained poorly understood. Particularly, given that GRP neurons are glutamatergic (Sun et al., 2017), it is unclear why deleting the GRPR can block itch behavior. Presumably, the release of GRP and its binding to GRPR acts in concert to the activation of postsynaptic glutamate receptors. In this issue of Neuron, the Zeilhofer group uses an elegant series of experimental approaches
Neuron 103, July 3, 2019 ª 2019 Elsevier Inc. 5
Neuron
Previews
Figure 1. Schematic Diagram Depicting How Pruritogens Can Elicit the Sensation of Itch Pruritogens activate their receptors in the peripheral terminals of pruriceptors located in the skin (the example of the MrgprA3-expressing pruriceptors is given here), which excites the sensory neuron and induces glutamate release at its central terminal in lamina II of the dorsal horn. This direct excitation of GRP-expressing neurons triggers a bursting behavior in these cells. The release of GRP from these neurons onto GRPR-expressing interneurons only occurs when GRP neurons burst, as opposed to single isolated action potentials. The binding of GRP to its receptor GRPR causes the inhibition of an inward rectifier potassium channel (Kir) that depolarizes the membrane voltage and brings it near the action potential threshold. When glutamate-elicited excitatory postsynaptic potentials (EPSPs) are superimposed on this depolarization, they reach the action potential threshold and the GRPR can then activate its downstream target, ultimately activating spinal projection neurons that carry the itch signal to supraspinal center.
to reveal the properties of the GRP-GRPR neuron synapse (Pagani et al., 2019). To examine the synaptic communication between these two subsets of neurons, they generated a triple transgenic mouse that expressed channelrhodopsin2-eYFP (ChR2-eYFP) fusion protein in GRP neurons and eGFP in GRPR neurons, allowing them to record from GRPR neurons while optogenetically stimulating GRP neurons and to confirm the monosynaptic nature of this communication. Interestingly, when postsynaptic responses of GRPR neuron were examined in response to single light pulse stimulation of GRP neurons, none of the excitatory GRPR neurons were able to generate action potentials. The excitation produced by such stimulation was restricted to subthreshold depolarizations, leading Pagani et al. (2019) to question whether such activation modality truly reflects the activity of GRP neurons activated by peripheral pruriceptors. They thus generated another triple transgenic mouse line in which MrgprA3expressing pruriceptors expressed ChR2 and GRP neurons expressed eGFP. This enabled them to record, in spinal cord slice preparations, from GRP neurons 6 Neuron 103, July 3, 2019
while stimulating the central terminals of the primary pruriceptors. Surprisingly, their current-clamp recordings indicated that a single (4 ms) light pulse stimulation of MrgprA3 fibers triggered bursts of 2–5 action potentials in GRP neurons. This observation prompted them to determine whether burst-like firing in GRP neurons would be more appropriate when communicating with downstream GRPR neurons. They therefore mimicked this firing pattern in their subsequent experiments on synaptic communication between GRP and GRPR neurons. Through the use of temporally patterned optogenetic light stimulation, they tested whether burst-like stimulation of GRP neurons would produce action potentials in GRPR neurons. Surprisingly, this led to the gradual depolarization of GRPR neurons followed by the generation of action potentials. Furthermore, the depolarization and spontaneous activity that were generated persisted for minutes after the synaptic stimulation had stopped. To examine whether the gradual depolarization and excitation produced by burst-like activity in GRP neurons was due to GRP release or to glutamate receptor-dependent plasticity, they repeated
the experiments in the presence of GRPR or AMPA/NMDA receptor antagonists, respectively. The progressive depolarization and excitation persisted in the presence of glutamate receptor antagonists but were almost completely abolished by GRPR antagonists, thus highlighting the critical role of peptidergic signaling at this synapse. The metabotropic signaling pathway engaged by GRP was examined by exogenous application of the peptide and indicated that the depolarization was associated with an increase in input resistance, suggesting that some background potassium channels had closed. Through a series of pharmacological and electrophysiological approaches, these channels were identified as Kir-like and Kv4.2-like potassium channels (Figure 1). From these findings, Pagani et al. (2019) predicted that burst-like activity in GRP neurons was necessary to elicit GRP release, which would produce spiking in excitatory GRPR neurons and lead to the activation of spinal relays of pruriceptive information. To test this prediction in vivo, they chronically implanted GRP-ChR2 mice with fiber optics directed toward the dorsal horn and stimulated GRP neurons with brief pulses of light, applied either as a single stimulus or as a burst. Their results indicated that only during burst-like stimulation of GRP neurons was an aversive reaction elicited in the animals. This effect occurred with a certain delay and outlasted the stimulation period by several minutes, in agreement with the different time courses of pain and itch responses. The past decade has seen important advances in our understanding of how itch is perceived at the molecular level and how it is transmitted to the nervous system at the circuit level. A more challenging task has been to understand how these mechanisms differ from those involved in pain transmission in their necessity for peptidergic transmission. This involves a careful examination of the synaptic physiology of these synapses. Through a ‘‘tour de force’’ approach involving the generation of triple transgenic mice, in vivo optogenetic modulation of itch pathways and slice electrophysiology, the Zeilhofer lab identified a mechanism that explains how the synaptic transmission of itch signals differs
Neuron
Previews from pain signals. Future research may explain how this intracellular cascade can interact with others activated in GRPR neurons. For instance, it was recently demonstrated that these neurons also express the kappa-opioid receptor (KOR), whose activation can desensitize GRPR (Munanairi et al., 2018). Finally, the findings of the Zeilhofer lab open interesting avenues for integrating the unique role of the synapse between spinal GRP and GRPR neurons in the pathophysiology of chronic itch. REFERENCES Albisetti, G.W., Pagani, M., Platonova, E., Ho¨sli, L., Johannssen, H.C., Fritschy, J.M., Wildner, H., and Zeilhofer, H.U. (2019). Dorsal horn gastrinreleasing peptide expressing neurons transmit
spinal itch but not pain signals. J. Neurosci. 39, 2238–2250. Dong, X., Han, S., Zylka, M.J., Simon, M.I., and Anderson, D.J. (2001). A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106, 619–632. Han, L., Ma, C., Liu, Q., Weng, H.J., Cui, Y., Tang, Z., Kim, Y., Nie, H., Qu, L., Patel, K.N., et al. (2013). A subpopulation of nociceptors specifically linked to itch. Nat. Neurosci. 16, 174–182. Huang, J., Polga´r, E., Solinski, H.J., Mishra, S.K., Tseng, P.Y., Iwagaki, N., Boyle, K.A., Dickie, A.C., Kriegbaum, M.C., Wildner, H., et al. (2018). Circuit dissection of the role of somatostatin in itch and pain. Nat. Neurosci. 21, 707–716. Kardon, A.P., Polga´r, E., Hachisuka, J., Snyder, L.M., Cameron, D., Savage, S., Cai, X., Karnup, S., Fan, C.R., Hemenway, G.M., et al. (2014). Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82, 573–586.
Mack, M.R., and Kim, B.S. (2018). The itch-scratch cycle: a neuroimmune perspective. Trends Immunol. 39, 980–991. Munanairi, A., Liu, X.Y., Barry, D.M., Yang, Q., Yin, J.B., Jin, H., Li, H., Meng, Q.T., Peng, J.H., Wu, Z.Y., et al. (2018). Non-canonical opioid signaling inhibits itch transmission in the spinal cord of nice. Cell Rep. 23, 866–877. Pagani, M., Albisetti, G.W., Sivakumar, N., Wildner, H., Santello, M., Johannssen, H.C., and Zeilhofer, H.U. (2019). How gastrin-releasing peptide opens the spinal gate for itch. Neuron 103, this issue, 102–117. Sun, Y.G., Zhao, Z.Q., Meng, X.L., Yin, J., Liu, X.Y., and Chen, Z.F. (2009). Cellular basis of itch sensation. Science 325, 1531–1534. Sun, S., Xu, Q., Guo, C., Guan, Y., Liu, Q., and Dong, X. (2017). Leaky gate model: intensitydependent coding of pain and itch in the spinal cord. Neuron 93, 840–853.e5.
Neuron 103, July 3, 2019 7