Histamine induced itch and its relationship with pain

Histamine-induced itch and its relationship with pain - Semantic Scholar

histamine induced itch and its relationship with pain

Histamine-induced itch and alloknesis (itchy skin) in atopic eczema patients and controls. Heyer G, Ulmer FJ, Schmitz J, et al. Acta Derm Venereol (Stockh) Mol Pain. Jul 31; doi: / Histamine-induced itch and its relationship with pain. Shim WS(1), Oh U. Author information. In this review, we discuss the molecular mechanism and the pharmacological aspects of histamine-induced itch. Especially, the underlying mechanism of.

On the other hand, stimulation of phospholipase A2 PLA2 by H1R was found to mediate histamine-induced sensory neuron excitation [ 2930 ]. Histamine induces inward currents that are blocked by antagonists of TRPV1, a nonselective cation channel stimulated by capsaicin [ 3031 ]. More importantly, histamine-induced scratching is significantly lower in TRPV1-deficient mice [ 30 ]. However, as mentioned above, the role of H2R in itch appears minor.

However, it should be noted that H3R is predominantly expressed in the central nervous system, and was first identified in brain [ 37 ].

Although its existence in perivascular nerve terminals has been suggested [ 38 ], it appears that H3R is not present in the peripheral nervous system — at least in mice [ 23 ]. Therefore, the role of H3R in the mediation of histamine-induced itch seems minor. However, interestingly, H3R is regarded as a novel target for the treatment of obesity and cognitive disorders [ 3940 ].

The importance of H4R in terms of itch is becoming more evident [ 4142 ]. Moreover, the existence of H4R in sensory neurons is suggested by the observation that an intradermally administered H4R-specific agonist elicited scratching in mice, which were completely inhibited by pretreatment of H4R antagonist, JNJ [ 25 ].

Neurophysiology of itch fibers Most C fibers are polymodal nociceptors that respond to noxious mechanical and heat stimuli CMH units. These CMH units are mainly related to nociception, but are largely insensitive to or only weakly activated by histamine [ 44 ]. In addition, histamine-sensitive C-fibers do not respond to mechanical stimulation, which indicates that these itch-mediating fibers differ from polymodal C-fibers [ 45 ]. Indeed, these itch-mediating C fibers only comprise about five percent of afferent C-fibers in human cutaneous nerves [ 5 ].

Histamine activates a subset of C-fibers that innervate the superficial layer of skin and transmit electrical signals to the superficial layer of the dorsal horn of the spinal cord [ 5 ].

These signals then ascend to the thalamus through contralateral spinothalamic tracts and are eventually conducted to the somatosensory and cingulate cortex [ 46 ]. Interestingly, it was found that gastrin-releasing peptide plays a key role in mediating itch sensation, rather than pain, by interacting with gastrin-releasing peptide receptor GRPR at the spinal level [ 47 ].

Furthermore, the induction of scratching behavior in response to pruritogenic stimuli was significantly diminished in GRPR knockout mice, but pain-related behavioral responses to noxious stimuli were normal [ 47 ]. In addition, direct spinal injection of a GRPR antagonist considerably inhibited scratching behaviors [ 47 ]. Again, these results provide support for the presence of a distinct itch-mediating pathway. On the other hand, the itch elicited by cowhage a non-histaminergic pruritogen appears to be mediated through other distinct primary afferents [ 48 ] and through cowhage-specific non-histaminergic spinothalamic tracts [ 49 ].

Therefore, it seems that different types of itch-mediating neurons coexist in the periphery. Recently, the active compound in cowhage was identified as a novel cysteine protease "mucunain", which is a ligand for protease-activated receptors-2 and 4 [ 50 ]. Nakano et al recently similarly concluded that different types of dorsal horn neurons are associated with histamine-induced and protease-activated receptormediated itch [ 51 ]. Thus, it seems that there exist dedicated itch-mediating neuronal pathways.

histamine induced itch and its relationship with pain

Moreover, the recent identification of the co-existence of histamine-sensitive and insensitive or protease-related pathways may provide some insight into the mechanism of itch. Painful stimuli inhibits itch sensation We all share the experience that scratching relieves itching. Furthermore, itch is also relieved when noxious heat is administered [ 52 ].

Neural Plasticity

In other words, itch can be suppressed by painful mechanical and thermal stimuli. As stated above, itch- and pain-inducing stimuli activate distinct populations of sensory fibers, and thus, it is likely that painful stimuli modulate itch sensations centrally and not at the peripheral level.

Histamine was found not to induce itch when a noxious thermal stimulus was administered within 10 cm, or to reduce itch severity if a noxious stimulus was administered more than 10 cm away [ 53 ]. Noxious cold also reduces pruritus when administered to fingertips contralateral to a pruritic stimulus [ 54 ].

Moreover, various other painful stimuli, such as, noxious heat or scratching, are known to inhibit histamine-induced itch via central mechanisms [ 55 - 57 ]. In fact, capsaicin, the active ingredient of hot pepper, is used as an anti-pruritic agent [ 58 ]. Capsaicin activates the nonselective cation channel TRPV1, which is regarded to induce nociception [ 31 ].

Thus, it is assumed that the anti-pruritic effect of capsaicin is attributable to its algesic effect. However, it should be noted that TRPV1 is expressed in some histamine-sensitive itch-mediating fibers as well as nociceptive C-fibers [ 30 ], which raises the question; What types of processes are involved in the sensation experienced when capsaicin is applied to the skin? In fact, the clinical limitation of topical capsaicin administered as an anti-pruritic agent is that it produces unbearable, burning pain [ 58 ].

Furthermore, even if capsaicin excites TRPV1 in itch fibers, the itch sensation may not dominate since itch-mediating fibers comprise only small proportion of C fibers [ 5 ].

histamine induced itch and its relationship with pain

Thus, although capsaicin may activate both pain and itch through TRPV1 receptors in their respective neurons, it is highly likely that capsaicin preferentially activates nociceptive fibers. However, it should also be noted that repeated and prolonged applications of topical capsaicin are required to effectively reduce itch [ 6263 ].

  • Histamine-induced itch and its relationship with pain.
  • Histamine-induced itch and its relationship with pain

This method of application is believed to fully desensitize and deplete neuropeptides, such as, substance P in sensory afferents, and to thus delay the interconnection between skin and sensory neurons [ 58 ]. Indeed, it has been shown that repetitive application of topical capsaicin prevents histamine-induced itch under experimental conditions [ 64 ]. In this regard, it can also be considered that the anti-pruritic effect of capsaicin may stem from peripheral desensitization of sensory neurons and central mechanisms.

Itch can also be suppressed by cold stimuli [ 65 - 67 ], and in particular the anti-pruritic effect of menthol is interesting [ 65 ], because menthol activates cold receptor TRPM8 [ 6869 ]. However, although TRPM8 is a wonderful molecular target, the mechanism whereby cold and menthol mitigates itch has yet to be determined.

On the other hand, warming appears to aggravate itch. Indeed, histamine-induced response is potentiated by warming [ 67 ], but no clear explanation has been offered as to how these thermal stimuli interact with itch at the molecular level. It is noteworthy that some TRP channels, like TRPV3 [ 7172 ] respond to warming, which suggests that they participate in itch induction. However, no studies to date have focused specifically on this topic. Unfortunately, the relationships between itch and exogenous stimuli in disease states appear anything but straightforward.

For instance, the itch-inhibitory effects of repetitive scratching and noxious heat are ineffective in patients with atopic dermatitis [ 73 ].

Similarly, the inhibitory effect of topical capsaicin on histamine-induced itch was found to be ineffective in atopic dermatitis patients, but effective in healthy controls [ 64 ], indicating that other factors are involved in disease states. Moreover, in contrast to our general understanding that cooling alleviates itch, short-term low-intensity cooling increases the intensity of histamine-induced itch above the scratch threshold in man [ 7475 ]. Interestingly, as a corollary to the suppression of itch by painful stimuli, the reduction of pain by opioids may induce itch [ 76 ].

Currently, it is unclear why different opioids have different effects on itch. Nevertheless, it seems evident that itch can be enhanced when pain is suppressed, and suppressed when pain is enhanced, which demonstrates the existence of an intimate physiologic interaction between underlying causes of itch and pain sensations. Conclusion Itch is probably viewed as trivial malady by most, but to many patients itch is a distressing condition. Although it has been revealed by many researchers that there is a histamine-independent itch, this should not detract from the fact that histamine is deeply involved in various itch sensations.

Recent advances in molecular biology have helped reveal the key molecular players involved, but a considerable amount of effort will be required to determine how histamine-induced itch is mediated and can be inhibited. In our opinion, a thorough understanding of the pruritogenic actions of histamine is required if we are to resolved itch symptoms at the clinical level.

Competing interests The authors declare that they have no competing interests. Authors' contributions WS drafted the manuscript and UO revised the manuscript. References Hashiro M, Okumura M. Anxiety, depression and psychosomatic symptoms in patients with atopic dermatitis: Anxiety and depression in patients with chronic urticaria and generalized pruritus.

Red Wine Allergy and Histamine Intolerance Webinar - Sherry Torkos

Frontiers in pruritus research: The neurobiology of itch. Specific C-receptors for itch in human skin. Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. Properties of transdermal histamine iontophoresis: Opiate and H1 antagonist effects on histamine induced pruritus and alloknesis. Neuronal sensitization for histamine-induced itch in lesional skin of patients with atopic dermatitis. Recent patterns of medication use in the ambulatory adult population of the United States: Studies of the mechanism of acute vascular reactions to injury.

The relationship of mast cells and histamine to the production of edema by ovomucoid in rats. Histamine acts directly on calcitonin gene-related peptide- and substance P-containing trigeminal ganglion neurons as assessed by calcium influx and immunocytochemistry. Pharmacokinetics and antipruritic effects of hydroxyzine in children with atopic dermatitis.

Mode of action of H1 antihistamines in itch. Fexofenadine, an H1-receptor antagonist, partially but rapidly inhibits the itch of contact dermatitis induced by diphenylcyclopropenone in patients with alopecia areata.

histamine induced itch and its relationship with pain

Effects of histamine receptor antagonists on histamine-induced responses in human skin. Sensory responses of human skin to synthetic histamine analogues and histamine. Br J Clin Pharmacol. Involvement of histamine H4 and H1 receptors in scratching induced by histamine receptor agonists in Balb C mice.

Pharmacologic advances in the systemic treatment of itch. Pruritus-associated response mediated by cutaneous histamine H3 receptors. Involvement of histamine H3 receptors in scratching behaviour in mast cell-deficient mice. Role of substance P on histamine H 3 antagonist-induced scratching behavior in mice.

Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus.

TRPV1 and PLC Participate in Histamine H4 Receptor-Induced Itch

Histamine is one of the best-known endogenous mediators for the induction of itch. It is known that histamine receptors, which are found and cloned a class of G protein-coupled receptor so far, can be classified into four referred to as H1—4 [ 9 ].

H4 receptor is a new histamine receptor identified in [ 10 ]. The intradermally injected H4 receptors agonist 4-methylhistamine could induce itch in mice [ 12 ].

Furthermore, the H4 receptor agonist excites the mouse DRG neuron by increasing intracellular free calcium [ 14 ]. However, the mechanism of the H4 receptor in DRG neurons—a cluster of nerve cell bodies of peripheral sensory formation including itch—is not yet fully understood. Materials and Methods 2. The spinal cord was exposed and DRG from all spinal levels were dissected. Isolated ganglia were collected in a cold culture medium containing the following: DRG cells were dissociated by trituration using fire-polished Pasteur pipettes of decreasing tip pore size.

Cells were centrifuged at rpm for 5 min and resuspended in the culture medium, plated on glass cover slips pretreated with 0. Experiments were performed within the next 24 h. Fluorescence intensities at both wavelengths F and F were measured every 1—5 s, and images were obtained using PC-based software C-imaging systems; Hamamatsu Photonic.

Test compounds agonist or antagonist inhibitor were applied to these cells on the cover glass during scanning.