Histamine produces opposing effects to serotonin in the knee joint of rats

Formalin injected in the knee joint of rats produces concentration-dependent nociception, edema, and plasma leakage (PL). Herein, we investigated the effect of histamine H1 receptor (H1R) antagonists in this model. Articular nociception was inferred from the paw elevation time (PET; seconds) during 1-minute periods of stimulated walking, determined every 5 minutes, throughout a 60-minute experimental session. Edema was evaluated by the increase in articular diameter (AD; mm), and PL was measured by the amount of Evans blue dye in the synovial fluid (PL; μg/mL). Loratadine and cetirizine, given systemically, both increased the PET. None of the treatments changed the AD and PL. Loratadine given locally with formalin increased the PET but was without effect when given in the contralateral knee. Systemic loratadine was also without effect when formalin was coinjected with sodium cromoglycate. Histamine and the selective H1R agonist 2-pyridylethylamine decreased the PET and potentiated morphine spinal analgesia, but did not affect the AD and PL. Cetirizine prevented the antinociceptive effect of the H1R agonist. The N-methyl-D-aspartate/histamine-site agonist tele-methylhistamine coinjected with formalin only increased PET. Serotonin alone had no effect on the PET and increased the AD, and the highest dose increased the PL. When coinjected with formalin, serotonin only caused hypernociception, and the highest dose also increased AD. NAN 190, cyproheptadine, and ondansetron (respectively, 5-HT1, 5-HT2, and 5-HT3 receptor antagonists) decreased the PET without changing the AD or PL. Collectively, these results suggest that in rats, the H1R plays an antinociceptive role within the knee joint, while serotonin receptors play a pronociceptive role.

The present study revealed an antinociceptive mechanism that has previously not been detected by traditional nociceptive tests. Our observations may help to improve the development of new pharmacological strategies for the treatment of clinically relevant pains that generally originate in deep structures.