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Histaminergic Pharmacology Modulates the Analgesic and Antiedematogenic Effects of Spinally Injected Morphine

Stein, Taciane MSc; Souza-Silva, Eduardo MSc; Mascarin, Lucas BPharm; Eto, Carolina BPharm; Fin, Franci Ellen BPharm; Tonussi, Carlos Rogério DSc

doi: 10.1213/ANE.0000000000001326
Pain and Analgesic Mechanisms: Research Report

BACKGROUND: Histamine receptors are known to participate in spinal cord nociceptive transmission, and previous studies have suggested that histaminergic receptors are involved in the analgesic effects of morphine. Herein, we investigated the effect of intrathecal injection of histaminergic agonists and antagonists in a model of acute articular inflammation and their interaction with morphine.

METHODS: After carrageenan injection in the right knee joint, articular incapacitation was measured hourly, for up to 6 hours, by the paw elevation time during 1-minute periods of stimulated walking. Inflammatory edema was also assessed hourly by determining an increase in articular diameter. Spinal treatments were administered 20 minutes before knee-joint carrageenan injection and were compared with the saline-treated control group.

RESULTS: Intrathecally injected histamine increased incapacitation and articular edema, whereas the H1R antagonist, cetirizine, decreased both parameters. The H3R agonist, immepip, decreased both incapacitation and edema, but the H3R antagonist, thioperamide, increased both incapacitation and edema. Morphine inhibited both incapacitation and edema. Furthermore, combining a subeffective dose of morphine with cetirizine or immepip potentiated the analgesic and antiedematogenic effect.

CONCLUSIONS: Histamine seems to act at the spinal level via H1 and H3 receptors to modulate acute arthritis in rats. An H1R antagonist and H3R agonist were found to potentiate the analgesic and antiedematogenic effects of morphine, suggesting that histaminergic and opioid spinal systems may be explored for means of improving analgesia, as well as peripheral anti-inflammatory effects.

From the Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil.

Eduardo Souza-Silva, MSc, is currently affiliated with Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark.

Accepted for publication March 1, 2016.

Funding: Coordenação para o Aperfeiçoamento do Pessoal do Ensino Superior (CAPES) and Conselho Nacional de Pesquisa e Desenvolvimento (CNPQ).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Carlos Rogério Tonussi, DSc, Department of Pharmacology, CCB, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil. Address e-mail to

Histamine has an important role in pain sensation because it is involved in the modulation of nociceptive transmission in the central nervous system.1–4 Histaminergic neurons emerge exclusively from the tuberomammillary nucleus of the posterior hypothalamus and are sent through collateral projections to practically the entire brain and parts of the spinal cord.5,6 Intrathecal administration of histamine produces nociceptive behaviors in mice, consisting of scratching, biting, and licking.7,8 Histidine decarboxylase knockout mice have shown that animals depleted of histamine present a diminished behavioral response to several noxious stimuli.9 Molecular studies also support the notion that H1R plays an important role in these histamine effects.1

Histamine has also been implicated in the regulation of antinociception induced by opioids,10–13 and it has been suggested that the morphine increases histamine release from central histamine-containing axons.14,15 Pharmacological manipulation of opioid receptors and their intracellular signaling mechanisms in the spinal cord has been shown to modify peripheral inflammation.16–18 Several lines of evidence have shown that dorsal root reflex (DRR) generation is mainly responsible for the neurogenic component of inflammation. The DRR consists of antidromic action potentials running from the spinal cord dorsal horn toward the periphery through primary afferent nociceptors,19–21 which cause an increase in peripheral inflammation. Inhibition of the DRR may explain the peripheral anti-inflammatory effect of several pharmacological interventions in the spinal cord.22–25

Because spinal histamine can modulate nociception and effects of opioid, it is conceivable that it also can affect peripheral inflammation. In the present study, our aim was to investigate the possible spinal interaction of histamine and morphine in an articular inflammatory model in rats assessing both pain and inflammation end points.

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Experiments were performed on male Wistar rats (300–400 g), which were housed in a temperature-controlled room (21 ± 2°C) under a 12-/12-hour light/dark cycle with free access to water and food. All experiments were conducted according to the ethical guidelines of the International Association for the Study of Pain (IASP, 1983) and approved by the local ethical committee for animal research (CEUA/PP00368).

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The following substances were used: cetirizine (H1R antagonist), histamine, immepip (H3R agonist), and thioperamide (H3R antagonist) were from Sigma-Aldrich Brazil (São Paulo, SP, Brazil); morphine sulfate (Dimorf®) was from Cristália Produtos Químicos and Farmacêuticos Ltda. (Itapira, SP, Brazil); carrageenan was from BDH Chemicals Ltd. (Poole, UK). All drugs were diluted in sterile physiological saline.

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Carrageenan-Induced Knee-Joint Inflammation

Knee-joint inflammation was induced by a single injection of carrageenan dissolved at a concentration of 1 mg/mL in physiological saline. This solution was boiled for 1 to 2 seconds and cooled to room temperature. The injection site was previously shaved and topically disinfected with an iodine alcohol solution. Intra-articular injection of the carrageenan solution (50 μL) was given in the right knee joint using a 26-gauge needle.

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Articular Incapacitation

The rat knee-joint incapacitation test is described in detail elsewhere.26 In this test, rats are placed on a revolving cylinder (30 cm diameter; 3 rpm) for 1-minute periods, and a computer-assisted device measures the total time that a specific hind paw is not in contact with the cylinder surface (paw elevation time [PET]; seconds). Normally, control animals display a PET of 10 seconds on average, whereas knee-joint inflammation increases this value only in the affected limb. The PET was evaluated immediately before (baseline) and hourly after carrageenan injection for 6 consecutive hours.

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Articular Measurement

A micrometer gauge was used to measure the length of the knee-joint mediolateral axis and used as an index of inflammatory edema. Each measurement was taken at 3 arbitrary positions along the proximodistal line of the knee joint, and the highest value was registered. This measurement is called articular diameter, and the data are presented as the mean difference of the articular diameter values taken hourly after carrageenan injection from those taken just before (articular diameter increase [AD]; centimeters). Similar to PET, the 6-hourly AD measurements were made.

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Statistical Analysis

Statistical power test was applied to previous data to establish the sample size for both PET and AD, and a minimum of 6 animals was found for both parameters evaluated. All experiments were conducted with this sample size, excepting the experiment combining morphine with cetirizine and immepip, in which the sample size was 8. Statistical analysis was performed using the software Statistica 7.0 (StatSoft, Tulsa, OK). Data were expressed as the mean ± SEM and shown as bars in the figures. Both PET and AD bars represent the summation of 1 measurement made before carrageenan articular injection and the 6 consecutive measurements made hourly after. PET and AD comparisons were made by 1-way analysis of variance followed by the Duncan post hoc test. The experimenter was blinded to experimental treatment groups.

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Spinal Cord Histaminergic Modulation of Peripheral Inflammation

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

Histamine injection (0.02, 0.2, 2, 200, and 2000 pmol) in the lumbar spinal intrathecal space increased both arthritic incapacitation (2 pmol, P =0.030286; Fig. 1A) and the articular diameter elicited by carrageenan (2 pmol, P = 0.022804; Fig. 1B). In contrast, the H1R antagonist cetirizine (0.126, 1.26, 12.6, 126, and 1260 pmol) inhibited incapacitation (126 pmol, P = 0.005251; Fig. 2A) and the AD (126 pmol, P = 0.031724; Fig. 2B). Spinal injection of the H3R agonist immepip (0.04, 0.4, 4, and 32 nmol) produced the opposite effect from histamine, decreasing incapacitation (4 nmol, P = 0.014316; Fig. 3A) and the articular diameter (4 nmol, P = 0.0152273; Fig. 3B). In contrast, the H3R antagonist thioperamide (0.0004, 0.04, and 4 nmol) both enhanced the incapacitation induced by carrageenan (0.04 nmol, P = 0.033623, and 4 nmol, P = 0.031110; Fig. 4A) and increased the articular diameter (0.04 nmol, P = 0.004044; Fig. 4B).

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Interaction Between Morphine and Histaminergic Transmission in the Spinal Cord

Figure 5

Figure 5

Figure 6

Figure 6

Morphine (0.5, 5, and 45 nmol) administered in the lumbar spinal intrathecal space 20 minutes before intra-articular carrageenan decreased incapacitation (5 nmol, P = 0.000056, and 45 nmol, P = 0.0000064; Fig. 5A) and the articular diameter (45 nmol, P = 0.000702; Fig. 5B). Furthermore, combining a subanalgesic dose of morphine (0.5 nmol) with an equally subeffective dose either of the H3R agonist immepip (0.4 nmol) or of the H1R antagonist cetirizine (12.6 pmol) significantly decreased articular incapacitation although there was no significant effect on the articular diameter (morphine + immepip, P = 0.010291, and morphine + cetirizine, P =0.004411; Fig. 6, A and B). Similarly, combining a sub-antiedematogenic dose of morphine (5 nmol) with the same subeffective doses of immepip and cetirizine produced a potent inhibition of articular incapacitation (morphine + immepip, P = 0.000178, and morphine + cetirizine, P =0.003729; Fig. 6C) and also reduced articular diameter (morphine + immepip, P = 0.000029, and morphine + cetirizine, P =0.000049; Fig. 6D).

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In the present study, it was found that a spinally administered H1R antagonist or H3R agonist can inhibit articular nociception and peripheral edema induced by intra-articular carrageenan and that both agents can also potentiate similar effects produced by morphine. The present results suggest that spinal histamine is involved not only in nociceptive processing but also in the control of peripheral inflammation.

Tuberomammillary nucleus of hypothalamus projects histaminergic axons to the spinal cord,5,6 but the role of histamine at this level is still poorly studied. Three types of histamine receptors—H1, H2, and H3—are found in the superficial lamina I and II of the dorsal horn.27–29 These laminae receive nociceptive information from C and Aδ polymodal primary sensory fibers.30 The antinociceptive and pronociceptive effects of H1R and H3R antagonists suggest that histamine is continuously released in the spinal cord during articular inflammation and has an active role in the processing of nociceptive information with opposing effects mediated by these 2 receptor types.

Several lines of evidence support a role for histamine H1R in pain processing at the spinal level. H1R activation has been shown to play a pronociceptive role in the dorsal horn.1,3,7 Thus, intrathecal injection of H1R antagonist elicits analgesia,31 whereas spinally injected morphine produces a greater antinociceptive effect in H1R knockout mice,32 and it has been suggested that the activation of histamine H1R in the spinal cord can increase sensitivity to a painful stimulus. However, H3R activation in the spinal cord has been found to exert an antinociceptive effect.33 The present findings corroborate current knowledge about the role of this signaling pathway in nociception. However, the observed effects of these drugs on peripheral inflammation add a new perspective for the control of arthritic conditions. The spinal cord is known to be a center that controls peripheral inflammation by altering antidromic activity in primary afferent nociceptors.21 Histamine, by modulating nociceptive sensitivity in the spinal cord, could therefore play a role in such control of peripheral inflammation. This assumption is in line with our finding that spinal injection both the H1R antagonist, cetirizine, and the H3R agonist, immepip, reduced articular edema.

DRRs are action potentials generated in the central branches of nociceptors, mainly running antidromically to the peripheral terminal.21 This phenomenon enhances inflammation by the release of vasoactive peptides, for example, substance P and Calcitonin Gene-Related Peptide (CGRP)34 and probably prostaglandin E2.35,36 Our working hypothesis is that histamine can potentiate both nociception and the generation of DRR, which would explain the enhancement of incapacitation and articular edema, respectively, by acting on H1Rs. However, the action of H3R seems to be responsible for the antinociceptive and antiedematogenic effects.

Although H1R is positively coupled to the adenilate cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway,37 the H3R has the opposite effect and inhibits via Gi protein. H3R activation has been shown to inhibit adenylate cyclase activity, thus reducing cAMP and Ca2+ levels.38–40 Primary afferent nociceptor sensitization is a phenomenon directly linked to the AC/cAMP/PKA pathway activation in rats41,42 and also involves PKCε.41,43,44 Thus, the molecular signaling of both histamine receptors fits well with the idea that primary afferent sensitization by H1R activation is responsible for the increase in either nociception or peripheral edema, whereas its desensitization by H3R activation causes the opposite effect.

Several studies have suggested that histamine receptors are involved in some pharmacological actions of morphine.12,13,32 In additional previous reports, we have shown that spinal administration of morphine produced a potent inhibitory effect on the carrageenan-induced paw edema.13,16 The present data suggest that spinal injection of opioids can also produce potent antinociception and antiedematogenic effects in the carrageenan-induced arthritis model. Furthermore, both the H1R antagonist, cetirizine, and the H3R agonist, immepip, produced a positive interaction with morphine in terms of either antinociceptive or antiedematogenic effects.

These kinds of interactions between opioids and histamine for nociceptive modulation have been shown in additional previous reports. For example, H1R antagonists administered subcutaneously potentiated opiate analgesia,45,46 whereas antinociception induced by morphine was significantly augmented in H1R knockout mice.32 In addition, it has been reported that H3R antagonists attenuate the antinociceptive effect produced by morphine47 and β-endorphin,12 whereas the H3R agonist, R-α-methylhistamine, potentiates the morphine analgesic effect in mice.47

Systemically delivered morphine was shown to facilitate histamine release in the periaqueductal gray,15 and intracerebroventricular injection of morphine, or other opioids, increased the turnover of brain histamine, suggesting that morphine acts on brain opioid receptors to stimulate the activity of histaminergic neurons.48 Clinical studies have also demonstrated that spinal cord administration of morphine results in the release of histamine.49 Because histamine has consistently been shown to be pronociceptive in the spinal cord and at other brain levels, it is conceivable that morphine-induced analgesia is antagonized by histamine release. Taking these data into account, it would be expected that the coadministration of morphine with either an H1R antagonist or an H3R agonist would result in a potentiation of the analgesic effect, as observed here. Furthermore, such reasoning also predicts a similar interaction upon the antiedematogenic effect produced by spinal morphine administration, which was indeed shown in the present study. The observed opioid-induced antiedematogenic effect highlights the importance of this central mechanism of inflammatory control and the convergence of such mechanism with that of nociception.

In conclusion, the present study brings additional support for the existence of central nervous system control of peripheral inflammation, also suggesting a role for spinal histaminergic receptors. The blockade of H1R and activation of H3 autoreceptors might be explored therapeutically to enhance the efficacy of intrathecal morphine.

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Name: Taciane Stein, MSc.

Contribution: This author helped in experimental design, execution of the study, and prepare the manuscript.

Attestation: Taciane Stein is the archival author.

Name: Eduardo Souza-Silva, MSc.

Contribution: This author helped design the study.

Attestation: Eduardo Souza-Silva attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Lucas Mascarin, BPharm.

Contribution: This author helped experimental execution.

Attestation: Lucas Mascarin attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Carolina Eto, BPharm.

Contribution: This author helped experimental execution.

Attestation: Carolina Eto attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Franci Ellen Fin, BPharm.

Contribution: This author helped experimental execution.

Attestation: Franci Ellen Fin attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Carlos Rogério Tonussi, DSc.

Contribution: This author helped design the study and prepare the manuscript.

Attestation: Carlos Rogério Tonussi approved the final manuscript.

This manuscript was handled by: Jianren Mao, MD.

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