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.

Intestine motility, secretion, and constipation treatment principles

Introduction. Constipation is a derangement of the motor, secretory and/or evacuation function of the colon. The same symptoms are recorded in at least 20% of the population in the developed countries – as those occurring sporadically or for a long period.Basic content. The secretory function of the colon significantly affects stool consistency and its free movement. The secretion increases by 8–10 times in the presence of local mechanical irritation. Intestinal mucus is produced by colonic goblet cells. The frequency, time of defecation and stool consistency is in large part determined by the motor function of the colon. The relation of various types of contraction varies depending on the main function – propulsion or mixing. Rhythmic phasic contractions in the colon generate a pendular movement with slow propulsion of the contents and absorption of water. The tonic contractions enhance the mixing effect of weak rhythmic contractions. The propulsive contractions are specifically attributed to the lower gastrointestinal tract and occur spontaneously. They occur quite regularly, from 2 to 10 times a day, and ensure the propulsion of intestinal contents over great distances in the colon. When reaching the sphincter area, such wave causes its relaxation by mechanisms of descending inhibition. The dietary regime and adequate intake of carbohydrates with various chain lengths, including dietary fiber, as well as flavonoids and other components that modify peristaltic activity and secretion, play an important role in the regulation of intestinal secretion and peristalsis. The drugs enhancing intestinal secretion and peristalsis, such as bisacodyl and sodium picosulfate, are also used to treat constipation. These substances hydrolyse into bis-(p-hydroxyphenyl)-pyridyl-2-methane in the intestine, which, upon contact with the receptors in colonic mucosa, stimulates propulsive activity and increases intestinal secretion. The selective action of sodium picosulfate is confined to the colon.Conclusion. Pharmacological and non-pharmacological treatments for constipation are aimed at maintaining and enhancing the natural propulsive contractions of the colon and intestinal secretion.

The Effect of Pain Catastrophizing on Endogenous Inhibition of Pain and Spinal Nociception in Native Americans: Results From the Oklahoma Study of Native American Pain Risk

Background Conditioned pain modulation (CPM) is a task that involves measuring pain in response to a test stimulus before and during a painful conditioning stimulus (CS). The CS pain typically inhibits pain elicited by the test stimulus; thus, this task is used to assess endogenous pain inhibition. Moreover, less efficient CPM-related inhibition is associated with chronic pain risk. Pain catastrophizing is a cognitive-emotional process associated with negative pain sequelae, and some studies have found that catastrophizing reduces CPM efficiency. Purpose The current study examined the relationship between catastrophizing (dispositional and situation specific) and CPM-related inhibition of pain and the nociceptive flexion reflex (NFR; a marker of spinal nociception) to determine whether the catastrophizing–CPM relationship might contribute to the higher risk of chronic pain in Native Americans (NAs). Methods CPM of pain and NFR was assessed in 124 NAs and 129 non-Hispanic Whites. Dispositional catastrophizing was assessed at the beginning of the test day, whereas situation-specific catastrophizing was assessed in response to the CS, as well as painful electric stimuli. Results Situation-specific, but not dispositional, catastrophizing led to less NFR inhibition but more pain inhibition. These effects were not moderated by race, but mediation analyses found that: (a) the NA race was associated with greater situation-specific catastrophizing, which led to less NFR inhibition and more pain inhibition, and (b) situation-specific catastrophizing was associated with greater CS pain, which led to more pain inhibition. Conclusions Catastrophizing may contribute to NA pain risk by disrupting descending inhibition.

Enhanced Itch Intensity Is Associated with Less Efficient Descending Inhibition Processing for Itch But Not Pain Attenuation in Chronic Dermatology Patients

Objectives The study aims were 1) to investigate the direction of mutual inhibitory pathways on itch intensity by utilizing conditioned pain modulation paradigms for pain and itch attenuation and 2) to explore whether itch severity is affected by the individual pain sensitivity profile, as well as pain scores reported during the tests and the past week. Design Cross-sectional. Setting Testing was conducted at the Department of Dermatology, Rambam Health Care Campus. Subjects Forty patients suffering from chronic skin disorders associated with itch and treated in the Dermatology Clinic at Rambam Health Care Campus participated in the study. Methods Efficacy of descending inhibition was evaluated by two conditioned pain modulation (CPM) paradigms: by pruriception (CPMItch) induced by cold and heat as counterstimuli to inhibit itch intensity and by nociception (CPMPain). Severity and interference of clinical pain were assessed using the Brief Pain Inventory (BPI). Results Robust CPMItch responses were obtained following the various noxious stimulations. No associations were observed between CPMPain and CPMItch, itch severity, skin disease severity, and clinical pain symptoms. According to the linear regression model, itch severity was independently associated with less efficient CPMItch (B = –0.750, P < 0.001) and more efficient CPMPain (B = 0.031, P = 0.016), which affects itch in opposing manners. Conclusions Findings indicate that the intrinsic capacity to inhibit pain and itch by exposure to exogenous noxious stimuli autonomously affects itch intensity in an opposing manner. These findings may shed new light on the mutual mechanistic similarity and dissimilarity between pain and itch and their hierarchy.