Joanna Wallengren

Effects of substance P, neurokinin A and calcitonin gene-related peptide in human skin and their involvement in sensory nerve-mediated responses

The effects evoked by intradermal injections of substance P (SP), neurokinin A (NKA) or calcitonin gene-related peptide (CGRP) were studied in 51 non-atopic subjects. SP and NKA produced flare and weal, and CGRP produced an indurated erythema. The reactions to SP were strong, the flare being maximal 3-5 min after injection and the weal after 10-15 min. NKA evoked a much weaker flare and a slightly weaker weal than did SP. CGRP produced a prominent long-lasting, indurated erythema with pseudopodia surrounded by a pallor edge. The mode of action of the three peptides was studied by pretreatment of the skin with the histamine-releasing compound 48/80, the H1-antagonist mepyramine or the local anesthetic xylocaine. The results suggest that mast-cell histamine and an intact sensory nerve supply are essential for the flare response to both SP and NKA. The weal response to SP was somewhat reduced by pretreatment with either 48/80 or xylocaine. The weal response to NKA, however, did not seem to depend upon either mast cells or sensory nerve fibres. The erythema evoked by CGRP was not suppressed by pretreatment with xylocaine, compound 48/80 or mepyramine, suggesting a direct action of CGRP on the blood vessels. The interaction between SP and CGRP was studied in subjects receiving a low dose of CGRP and increasing doses of SP or a low dose of SP and increasing doses of CGRP. CGRP did not potentiate the SP-evoked flare and weal and SP did not seem to enhance the response to CGRP.

Effects of capsaicin, bradykinin and prostaglandin E2 in the human skin

The actions and interactions of putative mediators of inflammation, such as substance P (SP), histamine, bradykinin and prostaglandins (PGE2) were studied in human skin. In addition, the effects of capsaicin were examined as it is known to release (and to deplete) SP and calcitonin gene‐related peptide from C‐fibres. The flare evoked by bradykinin was abolished by pretreatment with lignocain (local anaesthetic), compound 48/80 (mast‐cell histamine liberator), mepyramine (H1‐receptor antagonist) and indomethacin (cyclo‐oxygenase inhibitor) but was unaffected by atropine and ketanserin (serotonin antagonist). The weal response was not reduced by any of the drugs. The flare evoked by capsaicin was abolished by lignocaine and indomethacin but was unaffected by compound 48/80, mepyramine, atropine and ketanserin. The weal response was reduced by indomethacin. The flare response to bradykinin seems to reflect the activation of C‐fibres and associated mast cells, while the flare response to capsaicin seems to reflect the activation of C‐fibres only. Repeated injections of capsaicin and bradykinin produced tachyphylaxis (and cross‐tachyphylaxis) and greatly reduced the SP‐evoked flare. Capsaicin produced tachyphylaxis also after treatment of the skin with a local anaesthetic, suggesting that it develops independently of C‐fibre impulse flow. The tachyphylaxis produced by bradykinin and capsaicin seems to reflect the depletion of messenger peptides from the C‐fibres. The flare response to SP following capsaicin‐ or bradykinin‐induced desensitization gradually returned to normal after 5–8 weeks. The erythema evoked by PGE2 was reduced by 30% following pretreatment with lignocaine, mepyramine or compound 48/80. The dermal effects of prostaglandins seem to be partly indirect, involving C‐fibres and mast cells, and partly direct on the vascular bed. The importance of prostaglandins for C‐fibre‐mediated effects is reflected in the fact that indomethacin and acetylsalicylic acid were found to suppress axon‐reflex‐mediated responses.

Phototherapy reduces the number of epidermal and CGRP-positive dermal nerve fibres.

The purpose of this study was to gain an understanding of why phototherapy relieves itching. Skin samples (3 mm punch biopsies) from non-inflamed gluteal skin of 10 patients undergoing phototherapy were compared before and after 20 treatments. All the cutaneous nerve fibres here visualized by antibodies against PGP 9.5, sensory nerve fibres by antibodies against calcitonin gene-related peptide (CGRP) and capsaicin-sensitive primary nociceptive afferents by antibodies against VR1-receptor. Following treatment, the number of PGP 9.5-positive nerve fibres in the epidermis was reduced from 193 +/- 52 to 102 +/- 34 (p < 0.0001) and the number of CGRP-immunoreactive nerve fibres, which occurred only in dermis, was reduced from 28 +/- 15 to 22 +/- 7 (p = 0.04). The VR1-immunoreactive nerve fibres, some of them containing immunoreactivity to CGRP, were not affected. The success of phototherapy in combating itch may at least partly be linked with the reduction in the number of epidermal nerve fibres. The reduction in the number of CGRP-immunoreactive nerve fibres in the dermis may contribute to the beneficial effects of UV irradiation on the inflammatory process.

Neuroanatomy and neurophysiology of itch.

ABSTRACT:  The specific pathway of “pure,” histaminergic itch is traced from the mechano‐insensitive nerve fibers in the skin to their central cortical projections. Neuropathic itch created at different levels of this anatomical pathway is reviewed. In this review the present author discusses damage to pruritoceptors in the skin, entrapment syndromes, damage to spinal ganglia, nerve root impingement, injury of the spinal cord, and cerebral damage in the distribution of the middle cerebral artery, capsula interna, or thalamus. Itch in inflamed skin resulting from interactions between nerve transmitters and other mediators of inflammation is described.

Brachioradial pruritus: A recurrent solar dermopathy

Brachioradial pruritus (BRP) is a localized itch in the skin of the lateral aspects of the arms. It was first described and named by Waisman1 in 1968, who reported having 1 to 2 patients each year with this disorder in his dermatologic practice in southern Florida. Heyel2 reported 14 patients from Transvaal, South Africa, in 1984. Sixty-eight patients with BRP evaluated prospectively over a 5-year period, and 42 patients with BRP over a 2year period were reported from Hawaii.3,4 Twelve of 15 patients were successfully treated with topical capsaicin.3,5 BRP is often refractory to treatment with topical or oral costicosteroids and antihistamines.2,6 All the patients described earlier lived in the tropics or subtropics. There have been few reports of BRP from more temperate climates.6-8 This article reports 13 cases of BRP from the south of Sweden. All patients had bilateral, symmetric symptoms. They were treated with capsaicin in a randomized, double-blind, placebo-controlled trial.

Substance P antagonist inhibits immediate and delayed type cutaneous hypersensitivity reactions

The role of substance P (SP) in allergic reactions of the skin was investigated. Spantide, a competitive inhibitor of SP. was injected intracutaneously into the volar aspect of the forearm prior to the following challenges: benzalkonium chloride (irritant delayed reaction), tuberculin (immunological delayed reaction). UVB irradiation, benzoic acid (non‐immunological contact urticaria), different food allergens and latex (in patients with immunological contact urticaria). Only the immunological reactions of contact urticaria and the reaction to tuberculin were suppressed by the SP antagonist, indicating that SP is involved in their pathogenesis.

Prurigo : diagnosis and management.

Prurigo is a condition of nodular cutaneous lesions that itch (pruire) intensely. Although the acute form can be caused by insect stings, most of the subacute and chronic forms appear to be idiopathic. Toxic agents deposited in the skin by exogenous factors such as parasites, bacteria, or topically or orally administered drugs can induce itch. In susceptible individuals, physical mechanisms such as UV light can induce changes in epidermal innervation that result both in itch generally and in prurigo lesions. Prurigo is sometimes associated with atopy, pregnancy, internal diseases, malabsorption, or malignancy. Some forms of prurigo may be secondary to scratching. Emotional factors can also influence the perception of itch and induce prurigo by provoking scratching. These are the various specialized forms of prurigo, and there are certain others, such as prurigo pigmentosa, that have some ethnic preference. Topical treatments by corticosteroids, coal tar, bath photochemotherapy, UVB, cryotherapy, or capsaicin, as well as systemic regimens involving use of psoralen + UVA (PUVA), erythromycin, arotinoid acid, cyclosporine, chloroquine, dapsone, minocycline, naltrexone, azathioprine or thalidomide are used for the treatment of this condition. Psychotherapeutic agents to treat problems of mood that deteriorate prurigo are also prescribed. Combined sequential treatments for generalized, therapy-resistant cases need to be tailored to the exacerbations that occur and to provide maintenance treatment in order to enable the patient to withstand the intolerable itch.

Familial perifolliculitis capitis abscedens et suffodiens in two brothers successfully treated with isotretinoin

inflammatory papules (Fig. 1, B). The patient did not wish to continue on ciprofloxacin, however, because of a gastrointestinal upset and fatigue that he attributed to the medication. He was instructed to use gentamicin ointment under plastic wrap occlusion three times a day. The plaque on his arm continued to improve and 2 months after first beginning the ciprofloxacin, a follow-up examination revealed only cribiform scarring and postinflammatory hyperpigmentation (Fig. 1, C).

Occurrence of substance P, vasoactive intestinal peptide, and calcitonin gene-related peptide in dermographism and cold urticaria

SummarySubstance P (SP), calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP) were assayed in lesions and normal skin of patients with dermographism and cold urticaria utilizing suction-induced blisters. There was no difference in SP and VIP concentrations between challenged and control skin of urticaria patients. On the whole, however, the concentration of both neuropeptides, and VIP in particular, was higher in the urticaria patients than in control subjects. CGRP levels were not increased. SP and VIP in blood samples from veins draining challenged skin areas were below the detection limit. It is concluded that SP and VIP may potentiate histamine in wheal formation and thus contribute to the increased reactivity of the skin to trauma and temperature changes in patients with physical urticaria.

Psychosomatic factors in pruritus

Pruritus and psyche are intricately and reciprocally related, with psychophysiological evidence and psychopathological explanations helping us to understand their complex association. Their interaction may be conceptualized and classified into 3 groups: pruritic diseases with psychiatric sequelae, pruritic diseases aggravated by psychosocial factors, and psychiatric disorders causing pruritus. Management of chronic pruritus is directed at treating the underlying causes and adopting a multidisciplinary approach to address the dermatologic, somatosensory, cognitive, and emotional aspects. Pharmcotherapeutic agents that are useful for chronic pruritus with comorbid depression and/or anxiety comprise selective serotonin reuptake inhibitors, mirtazapine, tricyclic antidepressants (amitriptyline and doxepin), and anticonvulsants (gabapentin, pregabalin); the role of neurokinin receptor-1 antagonists awaits verification. Antipsychotics are required for treating itch and formication associated with schizophrenia and delusion of parasitosis (including Morgellons disease).