Circuit dissection of the role of somatostatin in itch and pain.

This is a very interesting study from the labs of Andrew Todd and Mark Hoon that dissects the role of the neuropeptide somatostatin and somatostatin-expressing neurons in itch and pain. Somatostatin is expressed in a small subset of primary sensory neurons in the DRG as well as in many dorsal horn excitatory interneurons. Using a multidisciplinary approach, including optogenetics, chemogenetics, neuronal ablation, and pharmacology, the authors demonstrate that somatostatin+ DRG neurons also express the itch-specific peptide Nppb. Activation of these neurons transmits signals via activation of Npr1 neurons (also expressing GRP) with subsequent activation of GRPR-expressing neurons in the dorsal horn. Strikingly, somatostatin+ DRG neurons suppress certain types of pain. In addition, somatostatin+ dorsal horn neurons also promote itch signal transmission by inhibiting inhibitory interneurons expressing dynorphin, leading to the potentiation of GRPR neurons. These findings suggest a more complex disinhibition mechanism.

This study along with several recent publications support an emerging picture of itch and pain circuits in the spinal cord: instead of a simple linear labeled line, itch and pain signal transmission involves significant cross talk between excitatory and inhibitory interneurons. Therefore, manipulating a group of neurons will affect both itch and pain often in opposing directions. The authors clarified the role of inhibitory B5-I interneurons in suppressing itch, a controversial point reported in previous studies. They showed that it is the dynorphin+ and not NOS+ subset of B5-I neurons that expresses somatostatin receptors and inhibits itch. This study also demonstrates that there are parallel and non-overlapping itch pathways (i.e., Nppb/somatostatin+ versus MrgprA3+ neurons) existing in the periphery. However, both primary itch-sensing neurons converge onto the same secondary neurons (i.e., Npr1/GRP+ neurons) in the dorsal horn (Sun et al., 2017 and the current study). This convergence of peripheral itch pathways is consistent with the current result that manipulating somatostatin/dynorphin neurons in the spinal cord also affects MrgprA3+ neuron-mediated itch such as chloroquine and SLIGRL itch. Finally, the current study and a study by Sun et al. reveal an interesting phenomenon where itch suppresses pain, highlighting a reciprocal push and pull relationship between pain and itch in the spinal cord.