Investigation into the role of histamine receptors in rodent antinociception

Lamberti, C.; Bartolini, Alessandro; Ghelardini, Carla; Malmberg-Aiello, P.

doi:10.1016/0091-3057(95)02051-9

Cited by 35 publications

(15 citation statements)

References 20 publications

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“…H 1 and H 2 receptors are thought to mediate this effect (Thoburn et al, 1994;Braga et al, 1996;Lamberti et al, 1996). Related to pain relief, H 2 receptors in the brain are activated as part of opioid and nonopioid antinociceptive mechanisms , especially when stress elicits or enhances these responses (Nalwalk and Hough, 1995).…”

Section: Antinociceptive Profile For Brain Histaminementioning

confidence: 99%

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

Hough¹,

Rice²

2010

J Pharmacol Exp Ther

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Histamine H 3 receptors (H 3 Rs), distributed within the brain, the spinal cord, and on specific types of primary sensory neurons, can modulate pain transmission by several mechanisms. In the skin, H 3 Rs are found on certain A␤ fibers, and on keratinocytes and Merkel cells, as well as on deep dermal, peptidergic A␦ fibers terminating on deep dermal blood vessels. Activation of H 3 Rs on the latter in the skin, heart, lung, and dura mater reduces calcitonin gene-related peptide and substance P release, leading to anti-inflammatory (but not antinociceptive) actions. However, activation of H 3 Rs on the spinal terminals of these sensory fibers reduces nociceptive responding to lowintensity mechanical stimuli and inflammatory stimuli such as formalin. These findings suggest that H 3 R agonists might be useful analgesics, but these drugs have not been tested in clinically relevant pain models. Paradoxically, H 3 antagonists/ inverse agonists have also been reported to attenuate several types of pain responses, including phase II responses to formalin. In the periaqueductal gray (an important pain regulatory center), the H 3 inverse agonist thioperamide releases neuronal histamine and mimics histamine's biphasic modulatory effects in thermal nociceptive tests. Newer H 3 inverse agonists with potent, selective, and brain-penetrating properties show efficacy in several neuropathic and arthritis pain models, but the sites and mechanisms for these actions remain poorly understood. Histamine and PainHistamine, found throughout the body in both neuronal and non-neuronal sources, can modify pain transmission by actions at multiple receptors in the skin, spinal cord, and brain. Rapidly expanding information on the distribution and functions of H 3 receptors (H 3 Rs) and the recent development of new H 3 R ligands have heightened interest in the possible modulation of pain by H 3 R-acting drugs. The present article provides a short, integrative overview of relevant studies (for review see also Sander et al., 2008;Tiligada et al., 2009;Gemkow et al., 2009). Measuring Pain in the LaboratoryPain, which can be defined as the central representation of tissue-damaging stimuli with sensory-discriminative, motivational, and cognitive components (Besson and Chaouch, 1987), is readily understood by humans as a sensory experience. Ideally, evaluation of the pain-relieving properties of drugs should directly measure reductions in pain perception. Instead, assessment of analgesic drug action in nonverbal subjects relies heavily on measures of behavioral, often reflexive, responses. Because drugs can modify these responses (but not necessarily the underlying perceptions), results from pain testing in laboratory animals can be misleading. The present limitations of preclinical methodologies for identifying pain-relieving drugs have been discussed previously Vierck et al., 2008).Notwithstanding the limitations in state-of-the-art analgesic testing, many factors must be considered when evaluating

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Section: Antinociceptive Profile For Brain Histaminementioning

confidence: 99%

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

Hough¹,

Rice²

2010

J Pharmacol Exp Ther

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“…Knockout mice lacking the histamine H 1 R showed significantly fewer responses to nociceptive stimuli compared to wild-type mice [11] . Other studies concerning histamine agonists and antagonists have demonstrated that these drugs can have different effects on the nociceptive threshold depending on their affinity for the histamine receptors and, therefore, on the administered dose [12][13][14] . Higher sensitivity to noxious stimuli was found after using a selective H 1 R agonist [15,16] , and modulation of nociception was demonstrated via activation of the H 2 R [12,17] .…”

Section: Introductionmentioning

confidence: 99%

Role of Histamine H<sub>3</sub> and H<sub>4</sub> Receptors in Mechanical Hyperalgesia following Peripheral Nerve Injury

Smith

Haskelberg

Tracey

et al. 2007

Neuroimmunomodulation

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Objective: Histamine is a chemical mediator that acts at four known types of histamine receptors and has been widely implicated in the development of nociception and neuropathic pain. Blocking histamine H₁ and H₂ receptors has been shown to reduce hyperalgesia following nerve injury, but the role of histamine H₃ and H₄ receptors in neuropathic pain has not been studied. Here, we used blockers of histamine H₃ and H₄ receptors to assess their effects on neuropathic pain behavior and mast cell numbers following peripheral nerve injury. In addition, we assessed the effect of activating H₄ receptors on neuropathic pain behavior. Methods: Rats were subjected to a partial ligation of the sciatic nerve, a model of neuropathic pain, and were treated either systemically or locally (hindpaw) with the H₃/H₄ receptor inverse agonist thioperamide, the specific H₄ receptor antagonist JNJ 7777120, or the H₄ receptor agonist VUF 8430. Measurements of mechanical hyperalgesia were carried out by Randall-Selitto test for 1–3 weeks, and sciatic nerve tissues were analyzed for numbers of intact mast cells by histology at 9 h after surgery. Results: Rats treated with thioperamide or JNJ 7777120 showed significantly enhanced mechanical hyperalgesia after partial ligation of the sciatic nerve. The number of intact mast cells in the injured nerve of these rats was higher than in control rats suggesting reduced mast cell degranulation, but was still significantly lower than in intact nerves. Rats treated with VUF 8430 showed significantly reduced mechanical hyperalgesia. Conclusion: We propose that the increase in mechanical hyperalgesia produced by thioperamide and JNJ 7777120 and the decrease in mechanical hyperalgesia produced by VUF 8430 may represent a direct effect of these agents on mechanospecific primary afferents, or an indirect effect of these agents via injury-induced inflammation.

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“…routes of administration. To assess whether metoprine-induced antinociception was actually due to inhibition of histamine-N-methyltransferase, the use of antagonists for H 1 -or H 2 -receptors seemed not to be the most adequate means, because of their low selectivity among histamine receptors (Schwartz et al 1991;Lamberti et al 1996), and the reported antinociceptive activity for both H 1 -and H 2 -blockers (Rumore and Schlichting 1985;Netti et al 1988;Abacioglu et al 1993). On the contrary, the inhibition of endogenous histamine release by activation of the H 3 -autoreceptor with its agonist, (R)-a-methylhistamine, seemed a more appropriate approach.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, naloxone, administered at a dose able to antagonize completely morphine antinociception (Lamberti et al 1996), prevented the rise in the basal nociceptive threshold induced by dimethyl sulfoxide but did not affect the hot plate values of mice treated with both doses of BW 301 U. The lack of effect of (R)-a-methylhistamine on the rise in pain threshold induced by dimethyl sulfoxide, which resembles its inability to alter morphine-induced antinociception, rules out a nonspecific effect of the H 3 -receptor agonist and supports the hypothesis of BW 301 U antinociception deriving from histamine-N-methyltransferase inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, a loading with the precursor, L-histidine, can induce antinociception due to its conversion into histamine, while the histamine H 3 -receptor antagonist, thioperamide, can be antinociceptive by blocking the negative feed-back mechanism mediated by autoreceptors (Malmberg-Aiello et al 1994). Two other molecules, impromidine and burimamide, which at low doses act as histamine H 3 -receptor antagonists (Lamberti et al 1996), have the same effect as thioperamide. On the other hand, antinociception related to the inhibition of histamine catabolism has been so far reported only for metoprine (MalmbergAiello et al 1994), previously described as a potent histamine-N-methyltransferase [EC 2.1.1.8] inhibitor (Duch et al 1978).…”

Section: Introductionmentioning

confidence: 99%

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Effects of two histamine-N-methyltransferase inhibitors, SKF 91488 and BW 301U, in rodent antinociception

Malmberg-Aiello

Lamberti

Ipponi

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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We have previously reported that the histaminergic system is involved in the control of pain perception, and that substances able to enhance histamine brain levels, such as the histamine-N-methyltransferase inhibitor, metoprine, induce antinociception. In the present study, in order to corroborate the idea of inducing antinociception by inhibiting histamine catabolism, the effects of a noncompetitive histamine-N-methyltransferase inhibitor. SKF 91488, were studied in rodents by means of tests inducing three different kinds of noxious stimuli: thermal (mouse hot plate), chemical (mouse abdominal constrictions) and mechanical (rat paw pressure). The ability to react to noxious stimuli was assessed by the rota-rod test. In addition, a competitive inhibitor of the histamine catabolism enzyme, BW 301 U, was studied in the hot plate test. SKF 91488 (30, 50 and 100 micrograms per animal i.c.v.) raised dose-dependently the pain threshold in all three tests. To verify whether SKF 91488-induced antinociception is due to inhibition of histamine-N-methyltransferase, (R)-alpha-methylhistamine, described to block histamine release and synthesis by stimulating the histamine H3-autoreceptor and activating the negative feed-back mechanism, was used. When administered at doses which do not alter the pain threshold per se, 0.5 microgram per rat i.c.v. or 10 mg kg-1 i.p. in mice, (R)-alpha-methylhistamine was able to antagonize significantly the antinociceptive effect induced by 30 micrograms per animal i.c.v. of SKF 91488. BW 301 U (30 and 100 mg kg-1 i.p.) showed a dose-dependent, long-lasting antinociception, which was also antagonized by pretreatment with (R)-alpha-methylhistamine. The present data show that the antinociceptive effect previously described for metoprine is not restricted to this molecule, but is also shared by other histamine-N-methyl-transferase inhibitors. This generalization provides further evidence to the importance of the histaminergic system in pain control mechanisms.

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Investigation into the role of histamine receptors in rodent antinociception

Cited by 35 publications

References 20 publications

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

Role of Histamine H<sub>3</sub> and H<sub>4</sub> Receptors in Mechanical Hyperalgesia following Peripheral Nerve Injury

Effects of two histamine-N-methyltransferase inhibitors, SKF 91488 and BW 301U, in rodent antinociception

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Investigation into the role of histamine receptors in rodent antinociception

Cited by 35 publications

References 20 publications

H3 Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

H3 Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

Role of Histamine H<sub>3</sub> and H<sub>4</sub> Receptors in Mechanical Hyperalgesia following Peripheral Nerve Injury

Effects of two histamine-N-methyltransferase inhibitors, SKF 91488 and BW 301U, in rodent antinociception

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H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

H₃ Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions