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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

© 2016 International Anesthesia Research Society