Descending inhibition of itch by neurokinin 1 receptor (Tacr1) -expressing ON cells in the rostral ventromedial medulla

The rostral ventromedial medulla (RVM) is important in descending modulation of spinal nociceptive transmission, but it is unclear if these descending pathways also modulate spinal pruriceptive transmission. RVM ON cells are activated by noxious algesic and pruritic stimuli and are pronociceptive. Many RVM-spinal projection neurons express the neurokinin-1 receptor (Tacr1), and ON-cells are excited by local administration of substance P (SP). We hypothesized that Tacr1-expressing RVM ON cells exert an inhibitory effect on itch opposite to their pronociceptive action. Intramedullary microinjection of SP significantly potentiated RVM ON cells and reduced pruritogen-evoked scratching while facilitating mechanical nociception. Chemogenetic activation of RVM Tacr1-expressing RVM neurons also reduced acute pruritogen-evoked scratching behavior while enhancing mechanonociception. Optotagging experiments confirmed RVM Tacr1-expressing neurons to be ON cells. We conclude that Tacr1-expressing ON cells in RVM play a significant role in the descending inhibition of spinal pruriceptive transmission.

Central circuit mechanisms of itch

Itch, in particular chronic forms, has been widely recognized as an important clinical problem, but much less is known about the mechanisms of itch in comparison with other sensory modalities such as pain. Recently, considerable progress has been made in dissecting the circuit mechanisms of itch at both the spinal and supraspinal levels. Major components of the spinal neural circuit underlying both chemical and mechanical itch have now been identified, along with the circuits relaying ascending transmission and the descending modulation of itch. In this review, we summarize the progress in elucidating the neural circuit mechanism of itch at spinal and supraspinal levels.

An investigation into the noradrenergic and serotonergic contributions of diffuse noxious inhibitory controls in a monoiodoacetate model of osteoarthritis

Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play. Therefore, this study considers the central contributions of chronic pain, using a monoiodoacetate (MIA) model of OA. Particularly, this study explores the functionality of descending controls over the course of the model by assessing diffuse noxious inhibitory controls (DNIC). Early-phase MIA animals have a functional DNIC system, whereas DNIC are abolished in late-phase MIA animals, indicating a dysregulation in descending modulation over the course of the model. In early-phase animals, blocking the actions of spinal α2-adrenergic receptors completely abolishes DNIC, whereas blocking the actions of spinal 5-HT7 receptors only partially decreases the magnitude of DNIC. However, activating the spinal α2-adrenergic or 5-HT7 receptors in late-phase MIA animals restored DNIC-induced neuronal inhibition. This study confirms that descending noradrenergic signaling is crucial for DNIC expression. Furthermore, we suggest a compensatory increase in descending serotonergic inhibition acting at 5-HT7 receptors as the model progresses such that receptor activation is sufficient to override the imbalance in descending controls and mediate neuronal inhibition. NEW & NOTEWORTHY This study showed that there are both noradrenergic and serotonergic components contributing to the expression of diffuse noxious inhibitory controls (DNIC). Furthermore, although a tonic descending noradrenergic tone is always crucial for the expression of DNIC, variations in descending serotonergic signaling over the course of the model mean this component plays a more vital role in states of sensitization.

Effects of pruritogens and algogens on rostral ventromedial medullary ON and OFF cells

Rostroventromedial medulla (RVM) ON and OFF cells are thought to facilitate and inhibit spinal nociceptive transmission, respectively. However, it is unknown how ON and OFF cells respond to pruritic stimuli or how they contribute to descending modulation of spinal itch signaling. In pentobarbital sodium-anesthetized mice, single-unit recordings were made in RVM from ON and OFF cells identified by their respective increase or decrease in firing that occurred just before nocifensive hindlimb withdrawal elicited by paw pinch. Of RVM ON cells, 75% (21/28) were excited by intradermal histamine, 50% (10/20) by intradermal chloroquine, and 75% (27/36) by intradermal capsaicin. Most chemically responsive units also responded to a scratch stimulus applied to the injected hindpaw. Few ON cells responded to intradermal injection of vehicle (saline: 5/32; Tween 2/17) but still responded to scratching. For OFF cells, intradermal histamine and scratching inhibited 32% (6/19) with no effect of histamine in the remainder. Intradermal chloroquine inhibited 44% (4/9) and intradermal capsaicin inhibited 61% (11/18) of OFF cells. Few OFF cells were affected by vehicles (Tween: 1 inhibited, 7 unaffected; saline: 3 excited, 1 inhibited, 8 unaffected). Both ON and OFF cells that responded to one chemical usually also responded to others, whereas units unresponsive to the first-tested chemical tended not to respond to others. These results indicate that ascending pruriceptive signals activate RVM ON cells and inhibit RVM OFF cells. These effects are considered to facilitate and disinhibit spinal pain transmission, respectively. It is currently not clear if spinal itch transmission is similarly modulated.NEW & NOTEWORTHY The rostroventromedial medulla (RVM) contains ON and OFF cells that are, respectively, excited and inhibited by noxious stimuli and have descending projections that facilitate and inhibit spinal nociceptive transmission. Most RVM ON cells were excited, and OFF cells inhibited, by intradermal injection of the pruritogens histamine and chloroquine, as well as the algogen capsaicin. These results indicate that itchy stimuli activate RVM neurons that presumably give rise to descending modulation of spinal itch transmission.