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

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.

Detection of blood flow perfusion and post - occlusive reactive hyperemia in the skeletal muscle of rats.

AIMS: Post-occlusive reactive hyperemia (PORH) remains poorly understood in the skeletal muscle system. This study was designed to validate an alternative strategy of PORH detection in rodents. Additionally, we explored the hypothesis that PORH is influenced by experimental models associated with impaired function of the skeletal muscle. MATERIALS AND METHODS: Wistar rats were anesthetized, and blood flow was assessed by laser Doppler in the anterior tibialis muscle, before and immediately after 5 s, 30 s, 3 min, or 5 min of flow occlusion, obtained through a cuff inflated to 300 mmHg around the thigh of the animals. KEY FINDINGS: In healthy animals, deflating the cuff resulted in a fast increment of local blood flow, characterizing the PORH after 5 s to 5 min of cuff occlusion and its dependence on flow occlusion duration. Importantly, we found different profiles of PORH in animals pretreated with reserpine (accelerated peak and reduced half recovery time), streptozotocin (increased peak), or subjected to muscle contraction in stretching (delayed peak), approaches used as experimental models to study fibromyalgia, type II diabetes mellitus, and soreness induced by unaccustomed eccentric exercise, respectively. SIGNIFICANCE: We demonstrated that the profile of PORH in the anterior tibialis muscle of rats is sensitive to a variety of experimental models often associated with the skeletal muscle functionality, providing a useful strategy to explore how and whether changes in local regulation of blood flow can contribute to the development of skeletal muscle associated symptoms in clinically relevant conditions.

Intra-articular injection of 2-pyridylethylamine produces spinal NPY-mediated antinociception in the formalin-induced rat knee-joint pain model.

Low doses of histamine or H1R agonist 2-pyridylethylamine (2-PEA) into the knee-joint were found to decrease formalin-induced articular nociception in rats. In this study, we evaluated the participation of spinal NPY in the antinociceptive effect produced by 2-PEA. Injection of formalin (1.5%) into one of the knee-joints causes the limping of the respective limb due to nociception, which was registered each 5 min over 60 min. Neuropeptide Y1 receptor (Y1R) content in the spinal cord was evaluated by western-blotting. Intrathecal (i.t.) injection of Y1R agonist Leu31, Pro34-NPY (0.7-7 µmol) decreased nociception, while injection of the antagonist BIBO 3304 (4 µmol), increased nociception. Antinociception produced by 2-PEA was reversed by a sub-effective i.t. dose of the Y1R antagonist. Similarly, this antinociceptive effect was prevented by i.t. pretreatment with the neurotoxin NPY-saporin (750 ng), which also reduced immunoblotting for Y1R in spinal cord homogenates. These data support the idea that antinociception induced by H1R agonists in the knee-joint of rats may be mediated by the spinal release of NPY, and this peptide seems to be acting via Y1R.

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

UNLABELLED: 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. PERSPECTIVE: 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.

Evaluation of the pro-inflammatory potential of nanostructured drug carriers in knee-joints of rats: effect on nociception, edema, and cell migration.

Nanocarriers have been developed aiming at drug delivery; however, the irritating effects of these nanoparticles on naïve or inflamed articular tissues are not known. Poly(D,L-lactide) (N-PLA), methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (N-PEG-PLA), and Dynasan 116 (SLN) were used to prepare the nanocarriers. The average diameter (nm) and zeta potential (mV) of these particles were, respectively, 251 and -33.2, 169 and -22.1, and 105 and -13.0. Naive or carrageenan-primed knee-joints received 100 microL of nanoparticle suspensions or control solution. Incapacitation and articular diameter were determined hourly. Synovial leukocytes were counted 6 h after nanoparticle injection. N-PLA increased the articular diameter and leukocytes, but did not cause incapacitation. In primed knee-joints, N-PLA caused incapacitation, and increased the articular diameter and leukocytes. SLN did not produce inflammatory signals either in naive or primed knees. In primed knee-joints, N-PEG-PLA presented an intermediate effect characterized by an increase in the articular diameter, and a slight increase of leukocytes, but not incapacitation. These results suggest that solid lipid nanoparticles may be safer than polymeric ones, which may be correlated to their chemical composition and superficial charge.

Skin-to-skin contact and/or oral 25% dextrose for procedural pain relief for term newborn infants.

OBJECTIVE: The goal was to compare the efficacy of oral 25% dextrose treatment and/or skin-to-skin contact for analgesia in term newborns during intramuscular injection of a hepatitis B vaccine. METHODS: A prospective, randomized, partially blinded, clinical trial was performed with 640 healthy term newborns. Infants at 12 to 72 hours of life were assigned randomly to receive an intramuscular injection of hepatitis B vaccine in the right thigh according to 4 analgesia groups, that is, no analgesia (routine); oral 25% dextrose treatment, given 2 minutes before the injection; skin-to-skin contact, initiated 2 minutes before the injection and persisting throughout the procedure; and a combination of the oral dextrose treatment and skin-to-skin contact strategies. For all groups, Neonatal Facial Coding System and Neonatal Infant Pain Scale scores were evaluated before the procedure, during thigh cleansing, during the injection, and 2 minutes after the injection. Premature Infant Pain Profile scores also were assessed for all infants. Pain scores were compared among the 4 groups. RESULTS: The use of oral 25% dextrose treatment reduced the duration of procedural pain in the studied population. Skin-to-skin contact decreased injection pain and duration. The combination of the 2 analgesic measures was more effective than either measure separately for term newborns. CONCLUSIONS: Nonpharmacologic analgesic measures were effective for the treatment of procedural pain in term infants. The combination of oral 25% dextrose treatment and skin-to-skin contact acted synergistically to decrease acute pain in healthy neonates.