Itching

Abstract: THE importance of prostaglandins in inflammation has been emphasized by the discovery that aspirin-like anti-inflammatory drugs inhibit their synthesis1–3. The anti-inflammatory and anti-pyretic effects of this group of drugs could be explained on this basis1, but their analgesic properties could not, then, be firmly linked to inhibition of prostaglandin synthesis. This was because the only subjective effect reported on intradermal injection of prostaglandin was a sensation of warmth and a slight itching*, and on the blister base PGE2 (up to 100 µg/ml.) failed to produce pain5. Several reports now describe the pain-producing activity of prostaglandins infused i.v. and injected intramuscularly6–8 in man. Collier and Schneider have shown that PGE1 is the most powerful agent in producing writhing responses in mice9. Vane1 suggested that rabbit aorta contracting substance (RCS)10 which may be the unstable cyclic peroxide intermediate in the biosynthesis of prostaglandins11, may be involved in the production of pain in inflammation. I tried to test this hypothesis by comparing the pain producing activity of fatty acid hydroperoxides with that of high concentrations of acetylcholine, bradykinin, histamine and PGE1 on intradermal injection in man. The intensity of the pain induced by the hydroperoxides was greater than that induced by the other agonists but for all except PGE1 the pain was transitory. On testing subdermal infusions to mimic the continuous release of an endogenous mediator of pain, two important properties of E-type prostaglandins were revealed. First, they increase the pain sensitivity to chemical and mechanical stimulation. Second, their effects are cumulative and depend not only on their concentrations but also on the time of exposure. The term “pain” is used to denote the overt pain evoked chemically during the infusions; hyperalgesia is used when pain was elicited only by applying slight pressure on the infusion area. Studies were carried out in five male volunteers each of whom received a full explanation of the nature of the experiment before giving his consent. The experiments were double blind.

Abstract: Itching, or pruritus, is defined as an unpleasant cutaneous sensation that serves as a physiological self-protective mechanism to prevent the body from being hurt by harmful external agents Chronic itch represents a significant clinical problem resulting from renal diseases and liver diseases, as well as several serious skin diseases such as atopic dermatitis The identity of the itch-specific mediator in the central nervous system, however, remains elusive Here we describe that the gastrin-releasing peptide receptor (GRPR) plays an important part in mediating itch sensation in the dorsal spinal cord We found that gastrin-releasing peptide is specifically expressed in a small subset of peptidergic dorsal root ganglion neurons, whereas expression of its receptor GRPR is restricted to lamina I of the dorsal spinal cord GRPR mutant mice showed comparable thermal, mechanical, inflammatory and neuropathic pain responses relative to wild-type mice In contrast, induction of scratching behaviour was significantly reduced in GRPR mutant mice in response to pruritogenic stimuli, whereas normal responses were evoked by painful stimuli Moreover, direct spinal cerebrospinal fluid injection of a GRPR antagonist significantly inhibited scratching behaviour in three independent itch models These data demonstrate that GRPR is required for mediating the itch sensation rather than pain, at the spinal level Our results thus indicate that GRPR may represent the first molecule that is dedicated to mediating the itch sensation in the dorsal horn of the spinal cord, and thus may provide a central therapeutic target for antipruritic drug development

Abstract: Itch and pain are two distinct sensations. Although our previous study suggested that gastrin-releasing peptide receptor (GRPR) is an itch-specific gene in the spinal cord, a long-standing question of whether there are separate neuronal pathways for itch and pain remains unsettled. We selectively ablated lamina I neurons expressing GRPR in the spinal cord of mice. These mice showed profound scratching deficits in response to all of the itching (pruritogenic) stimuli tested, irrespective of their histamine dependence. In contrast, pain behaviors were unaffected. Our data also suggest that GRPR+ neurons are different from the spinothalamic tract neurons that have been the focus of the debate. Together, the present study suggests that GRPR+ neurons constitute a long-sought labeled line for itch sensation in the spinal cord.

Abstract: Vasoneuroactive substances were applied through intradermal microdialysis membranes and characterized as itch- or pain-inducing in psychophysical experiments. Histamine always provoked itching and rarely pain, capsaicin always pain but never itching. Prostaglandin E2 (PGE2) led preferentially to moderate itching. Serotonin, acetylcholine, and bradykinin induced pain more often than itching. Subsequently the same substances were used in microneurography experiments to characterize the sensitivity profile of human cutaneous C-nociceptors. The responses of 89 mechanoresponsive (CMH, polymodal nociceptors), 52 mechanoinsensitive, histamine-negative (CMiHis−), and 24 mechanoinsensitive, histamine-positive (CMiHis+) units were compared. CMiHis+ units were most responsive to histamine and to PGE2 and less to serotonin, ACh, bradykinin, and capsaicin. CMH units (polymodal nociceptors) and CMiHis−units showed significantly weaker responses to histamine, PGE2, and acetylcholine. Capsaicin and bradykinin responses w...