Antihistamines as analgesics

The term 'neurogenic inflammation' has been adopted to describe the local release of inflammatory mediators, such as substance P and calcitonin gene-related peptide, from neurons. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. The aim of this review is to summarize the most recent findings on the role of histamine in neurogenic inflammation, with particular regard to nociceptive pain, as well as neurogenic inflammation in the skin, airways and bladder. LINKED ARTICLESThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 Abbreviations CGRP, calcitonin gene-related peptide; ERs, oestrogen receptors; GERD, gastro-oesophageal reflux disease; HDC, histidine decarboxylase; IC, interstitial cystitis; PBS, painful bladder syndrome; SP, substance P; VIP, vasoactive intestinal peptide IntroductionThe term 'neurogenic inflammation' describes the local release of inflammatory mediators, such as substance P (SP) and calcitonin gene-related peptide (CGRP), from afferent neurons. The initial evidence for neurogenic vasodilatation in response to noxious stimuli was obtained in the skin of humans and other mammals (Schmelz and Petersen, 2001), but now it is recognized that neurogenic inflammation also occurs in visceral organs. The inflammatory response evoked by the activation of the sensory nerve fibres, which includes local vasodilatation, plasma extravasation, leukocyte and platelet adhesion, and mast cell degranulation, is brought about by neuropeptides released from the peripheral endings of sensory neurons upon stimulation of the primary sensory terminals. Both SP in neurons and histamine in mast cells have a dual mediator role in neurogenic inflammation (Figure 1). In fact, as demonstrated by Foreman and Jordan (1984), injury causes activation of sensory nerve endings either directly or through the release of histamine from the adjacent mast cells. The action potential generated travels orthodromically to the dorsal horn of the spinal cord and spreads to other branches of the same neurons, which will then release SP from their terminals or varicosities. The released SP, as well as contributing itself to local vasodilatation, induces histamine release from the adjacent mast cells, which produces flare and further activates other sensory nerve endings (Foreman et al., 1983).Neutrophils, whose responsiveness to SP has been repeatedly demonstrated, contribute to the inflammatory soup following neurogenic inflammation. In fact, neutrophils express the SP receptors NK 1, NK2 and NK3, and when stimulated with SP induce the expression of COX-2 and PGE2 release in the nanomolar range (Gallicchio et al., 2008;. Furthermore, SP at micromolar concentrations primes neutrophils, thus en...

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“…However, clinical evidence is still lacking and previous trials obtained negative results (Raffa, 2001). …”

Section: Histamine Neurogenic Inflammation and Nociceptive Painmentioning

confidence: 99%

The role of histamine in neurogenic inflammation

Rosa

Fantozzi

2013

British J Pharmacology

170

138

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“…[2][3][4] However, the advent of various types of non-steroidal anti-inflammatory drugs (NSAIDs), and their rapid spread, seems to have discouraged such efforts to promote 1st AHs as analgesics.…”

Section: )mentioning

confidence: 99%

Analgesic Effects of 1st Generation Anti-histamines in Mice

Takahashi

Shima

Tsuchiya

et al. 2016

Biological & Pharmaceutical Bulletin

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Pain is sensed, transmitted, and modified by a variety of mediators and receptors. Histamine is a wellknown mediator of pain. In addition to their anti-histaminic effects, the classical, or 1st generation, anti-histamines (1st AHs) possess, to various degrees, anti-muscarinic, anti-serotonergic, anti-adrenergic, and other pharmacologic effects. Although there have been attempts to use 1st AHs as analgesics and/or analgesic adjuvants, the advent of non-steroidal anti-inflammatory drugs (NSAIDs) discouraged such trials. We previously reported that in patients with temporomandibular disorders, osteoporosis, and/or osteoarthritis, the analgesic effects of certain 1st AHs (chlorpheniramine and diphenhydramine) are superior to those of the NSAIDs flurbiprofen and indomethacin. Here, we compared analgesic effects among 1st AHs and NSAIDs against responses shown by mice to intraperitoneally injected 0.7% acetic acid. Since 1st AHs are water soluble, we selected water-soluble NSAIDs. For direct comparison, drugs were intravenously injected 30 min before the above tests. Histamine-H1-receptor-deficient (H1R-KO) mice were used for evaluating H1-receptor-independent effects. The tested 1st AHs (especially cyproheptadine) displayed or tended to display analgesic effects comparable to those of NSAIDs in normal and H1R-KO mice. Our data suggest that the anti-serotonergic and/or anti-adrenergic effects of 1st AHs make important contributions to their analgesic effects. Moreover, combination of a 1st AH with an NSAID (cyclooxygenase-1 inhibitor) produced remarkably potent analgesic effects. We propose that a 1st AH, by itself or in combination with a cyclooxygenase-1 inhibitor, should undergo testing to evaluate its usefulness in analgesia.

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“…It has been reported that histamine H 1 receptor knockout mice showed decreased sensitivity to nociceptive stimuli [2]. In the periphery, histamine release from the injured tissue, mast cells, and basophils led to activation of paintransmitting nerve fibers and also increases the release of pain-related neuropeptides [3]. The central histaminergic system plays an important role in the pain modulation.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Histamine H1 Receptor Antagonists on the Morphine-Induced Antinociception in the Acute Trigeminal Model of Nociception in Rats

Khalilzadeh

Azarpey

Hazrati

2016

Asian J Pharm Clin Res

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Objective: In this study, the effect of different classes of histamine H 1 receptor antagonists (chlorpheniramine, cetirizine, and fexofenadine), µ opioid receptor agonist (morphine), and opioid receptor antagonist (naloxone) in separate and combined treatments were investigated on the acute trigeminal model of pain in rats.Methods: Eye wiping test used for induction of acute trigeminal pain by putting a drop of NaCl, 5 M solution (40 µl) on the corneal surface of the eye, and the number of eye wipes counted during the first 30 seconds.Results: Intraperitoneal injection of both chlorpheniramine and cetirizine at doses of 10 and 20 mg/kg significantly inhibited the acute trigeminal pain. However, fexofenadine did not change corneal pain response. Morphine at doses of 1.25, 2.5, and 5 mg/kg reduced eye wipe responses. Administration of both chlorpheniramine and cetirizine but not fexofenadine before morphine-enhanced morphine analgesic activity, also pretreatment of animals with naloxone inhibited morphine, chlorpheniramine, and cetirizine-induced analgesia in the acute corneal pain. Conclusion:Our results showed that chlorpheniramine as a histamine H 1 antagonist that efficiently Penetrates blood-brain barrier (BBB) and cetirizine with less penetration of BBB but not fexofenadine (an H 1 receptor antagonist with a negligible brain-accessibility) could induce analgesia in the acute corneal pain via opioidergic mechanism. Coadministration of morphine with chlorpheniramine or cetirizine could enhance its analgesic activity in the acute trigeminal model of pain in rats.

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Antihistamines as analgesics

Cited by 54 publications

References 45 publications

The role of histamine in neurogenic inflammation

The role of histamine in neurogenic inflammation

Analgesic Effects of 1st Generation Anti-histamines in Mice

The Effect of Histamine H1 Receptor Antagonists on the Morphine-Induced Antinociception in the Acute Trigeminal Model of Nociception in Rats

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