Efeito analgésico de antagonistas do receptor da histamina H1 em modelo de dor provocada por formalina em ratos / Efecto analgésico de antagonistas del receptor de la histamina H1 en un modelo de dolor provocado por formalina en ratones / Analgesic effects of H1 receptor antagonists in the rat model of formalin-induced pain

JUSTIFICATIVA E OBJETIVOS: Os receptores de histamina mediam vias nociceptivas principalmente no sistema nervoso central. Alguns estudos mostraram efeito analgésico de antagonistas de receptor de histamina no sistema nervoso periférico. Não está claro se o efeito analgésico local é classe específico ou droga específico. MÉTODO: Para responder a essa questão, utilizamos três diferentes antagonistas do receptor H1 (pirilamina, prometazina e cetirizina) administrados diretamente na pata do rato, pela via intraperitoneal ou por bloqueio de nervo periférico em modelo de dor induzida por formalina. Observamos o efeito das drogas no comportamento do número de elevações da pata. RESULTADOS: Na fase I, a pirilamina local diminuiu o número de elevações da pata de forma dose-dependente. Na dose mais alta, a diminuição foi de 97,8 por cento. Para a prometazina, a diminuição foi de 92 por cento e para cetizirina, 23,9 por cento. Na fase II, a pirilamina diminuiu o número de elevações da pata em 93,5 por cento, a prometazina em 78,2 por cento e a cetirizina em 80,1 por cento. A administração dos fármacos por via intraperitoneal não alterou o comportamento doloroso. Quando utilizadas para bloqueio de nervo periférico, na fase I, a pirilamina diminuiu o número de elevações da pata em 96,7 por cento, a prometazina em 73,3 por cento e a cetirizina em 23,9 por cento. Na fase II, a pirilamina levou à diminuição de 86,6 por cento, a prometazina de 64,4 por cento e a cetirizina de 19,9 por cento. CONCLUSÕES: Os resultados mostraram que os antagonistas de receptor da histamina H1 apresentam efeitos analgésicos locais, diferentes do efeito sistêmico, sendo um deles anti-inflamatório e classe específico e o outro específico para prometazina e pirilamina, semelhante a efeito clínico anestésico local.

BACKGROUND AND OBJECTIVES: Histamine receptors mediate nociceptive pathways, especially in the central nervous system. Some studies have demonstrated the analgesic effects of histamine receptor antagonists in the peripheral nervous system. It is not clear whether the local analgesic effect is class-specific or drug-specific. METHODS: To answer this question, we used three different H1 receptor antagonists (pyrilamine, promethazine, and cetirizine) administered directly in the paw of the rat, intraperitoneally, or in peripheral nerve blockade in the formalin-induced pain model. The effects of the drugs on the number of paw elevations were observed. RESULTS: In phase I, the local administration of pyrilamine caused a dose-dependent reduction on the number of paw elevations; in the highest dose, the number of paw elevations was reduced by 97.8 percent. Promethazine decreased it by 92 percent, while cetirizine decreased by 23.9 percent. In phase II, pyrilamine decreased the number of paw elevations by 93.5 percent, promethazine by 78.2 percent, and cetirizine by 80.1 percent. Intraperitoneal administration of drugs did not change painful behavior. When used in peripheral nerve block, in phase I pyrilamine reduced the number of paw elevations by 96.7 percent, promethazine by 73.3 percent, and cetirizine by 23.9 percent. In phase II, pyrilamine reduced the number of paw elevations by 86.6 percent, promethazine by 64.4 percent, and cetirizine by 19.9 percent. CONCLUSIONS: The results demonstrate that H1 receptor antagonists have local analgesic effects, different from the systemic effects, one of them an anti-inflammatory and class-specific effect and the other similarly to the local anesthetic effect, specific for promethazine and pyrilamine

JUSTIFICATIVA Y OBJETIVOS: Los receptores de histamina intermedian las vías nociceptivas, principalmente en el sistema nervioso central. Algunos estudios arrojaron un efecto analgésico de antagonistas de receptor de histamina en el sistema nervioso periférico. No queda claro si el efecto analgésico local es de clase específico o un fármaco específico. MÉTODO: Para responder a esa pregunta, utilizamos tres diferentes antagonistas del receptor H1 (pirilamina, prometazina y cetirizina), administrados directamente en la pata del ratón, por vía intraperitoneal o por bloqueo de nervio periférico en modelo de dolor inducido por formalina. Observamos el efecto de los fármacos en el comportamiento del número de elevaciones de la pata. RESULTADOS: En la fase I, la pirilamina local redujo el número de elevaciones de la pata de forma dosis dependiente. En la dosis más alta, la reducción fue de un 97,8 por ciento. Para la prometazina, la disminución fue de un 92 por ciento y para la cetizirina de 23.9 por ciento. En la fase II, la pirilamina redujo el número de elevaciones de la pata en un 93,5 por ciento, la prometazina, un 78,2 por ciento y la cetirizina un 80,1 por ciento. La administración de los fármacos por vía intraperitoneal no alteró el comportamiento doloroso. Cuando se usaron para bloqueo del nervio periférico en la fase I, la pirilamina redujo el número de elevaciones de la pata en un 96,7 por ciento, la prometazina en un 73,3 por ciento y la cetirizina en un 23,9 por ciento. En la fase II, la pirilamina redujo un 86,6 por ciento, la prometazina un 64,4 por ciento y la cetirizina un 19,9 por ciento. CONCLUSIONES: Los resultados mostraron que los antagonistas del receptor de la histamina H1 presentaron efectos analgésicos locales, diferentes del efecto sistémico, siendo uno de ellos antiinflamatorio y clase específico, y el otro específico para la prometazina y la pirilamina, parecido con el efecto clínico anestésico local.

Ultrastructural Changes of Nerve Fibers Using a Neuropathic Pain Model in a Rat / 대한마취과학회지

BACKGROUND: Neuropathic pain is part of the symptom complex known as peripheral neuropathy. Sensory loss, muscle weakness, atrophy, and decreased tendon reflexes are more common than pain in neuropathic disease. Recently, Bennett and Xie reported that when the sciatic nerve of a rat is loosely ligated, the rat develops pain syndrome similar to that observed in neuropathic pain states in a human. Anatomical and physiological studies to date indicate that the major pathological finding in large diameter myelinated fibers distal to the ligatures was a complex loss of response while in small myelinated fibers there were was only subtle changes. However, a more extensive analysis of the various nerve fiber groups in the damaged sciatic nerve is required for a better understanding of the pathophysiology of the present neuropathy. METHODS: To evaluate the damage and regeneration of all caliber of peripheral nerve, we performed an electron microscopic analysis of the sciatic nerve after four loose ligatures were applied. Cross- sectional photomicrographies of regions distal to the ligatures were studied. A peripheral mononeuropathy was produced in adult rats by tying 4 ligatures loosely around the common sciatic nerve. The distal part of the ligated common sciatic nerve was severed in 2 rats of each group at 1 day, 3 days, 1 week, 2 weeks and 4 weeks respectively. The severed nerves were prepared for electron microscopic examination and pathologic changes were observed under the electron microscope. RESULTS: The ultrastructural changes after ligature application were as follows: At 1 day, the axon of A-beta fiber was shrunken and detached from the myelin sheath. C-fibers were mildly edematous and A-delta fibers appeared to be normal. On the 3rd day, the axoplasm of A-beta fibers was more shrunken, containing swelling of microorganelles and irregularly thickened myelin sheath. C-fiber showed some degrees of degeneration. A-delta fibers revealed mild degeneration and interstitial edema was also noted. At 1 week, the myelin sheaths of A-beta fibers were severely irregular in appearance with marked axonal loss. Many myelin fragments were phagocytosed in the cytoplasm of adjacent Schwann cells. At 2 weeks, A-beta fibers predominantly disappeared and many fragmented myelin sheaths were ingested in the Schwann cell. In some areas, A-beta fibers partially regenerated, which involved remyelination and an increase in the numbers of microorganelles of the Schwann cells. C-fibers were also regenerated. At 4 weeks after sciatic nerve ligation, A-beta fibers regenerated and myelin ovoids were noted within the axoplasm of the A-beta fibers. Myelin ovoids were found in the Schwann cell cytoplasm. A-delta fibers and C-fibers appeared ultrastructurally well-regenerated and had a relatively normal distribution. CONCLUSIONS: We found that maximal nerve degeneration was observed at 2 weeks after sciatic nerve ligation, thereafter, nerve regeneration was noted at 4 weeks after sciatic nerve ligation.

The Role of Peripheral N-Methyl-D-Aspartate (NMDA) Receptors in Freund's Complete Adjuvant Induced Mechanical Hyperalgesia in Rats / 대한마취과학회지

BACKGROUND: While the effects of excitatory amino acids have been characterized in the central nervous system, relatively little is known about their possible modulation of elements responsible for hyperalgesia within peripheral tissue. The purpose of this study was to investigate the role of excitatory amino acid receptors in mechanical hyperalgesia induced by a subcutaneous injection of Freund's complete adjuvant (FCA) into the rat hind paw. METHODS: Inflammations were induced by injecting FCA on the dorsal surface of the right hind paw of rats. Effects of excitatory aminoacid agonists or antagonists on mechanical hyperalgesia were investigated by a subcutaneous injection of a drug to the inflamed paw. Mechanical hyperalgesia was expressed as percent change in paw withdrawal threshold compared to baseline value that was measured before drug injection after inflammation was induced with FCA. RESULTS: In normal rats, an intraplantar (i.pl.) injection of L-glutamate, but not of D-glutamate (3 pmol/0.1 ml each) produced a mechanical hyperalgesia in the hind paw with a lowered paw paw-withdrawal threshold to pressure. In rats that developed the mechanical hyperalgesia associated with inflammation in the hind paw following an i.pl. injection of FCA (0.15 ml), the injection of a N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (1 pmol/0.1 ml) into the inflamed paw increased the paw pressure threshold (24.24.6% increase from baseline, P < 0.05). On the other hand, the injection of a non-NMDA receptor antagonist, 6-cyano-7-nitroqiunoxaline-2,3-dione (CNQX, 10 pmol/0.1 ml) into the inflamed paw had no effect on the FCA-induced lowering of the paw pressure threshold. CONCLUSIONS: The results suggest that NMDA, but not non-NMDA receptors play a substantial role in mediating the development of mechanical hyperalgesia induced in the inflamed paw following an i.pl. FCA injection.

Effect of Chemical Sympathectomy and Laser Radiation in the Neuropathic Pain / 대한마취과학회지

BACKGROUND: Treatments of neuropathic pain were included Ca blocker, steroid medication, epidural or spinal local anesthetics, intravenous reserpine and phenoxybenzamine and operative sympathectomy. This study was performed to evaluation the effects of laser radiation and intraperitoneal guanethidine to the neuropathic pain. METHODS: The neuropathic pain were produced by the tight ligation of L5 and L6 spinal nerves in the adult rats (Sprague-Dawley) withdrawl response to the non-noxious stimulation(mechanical allodynia) were increased and response to the cold stimulation (cold allodynia) were increased too. After that, we injected 50 mg/kg guanethidine intraperitoneally and radiated the He-Ne laser to the operated site to evaluate the effect of chemical sympathectomy and laser radiation. RESULTS: Mechanical allodynia was significantly reduced(p<0.05) 1st and 2nd day after chemical sympathectomy. Cold allodynia was significantly reduced(p<0.05) 1st day after chemical sympathectomy. Mechanical and cold allodynia were not significantly reduced after laser radiation. CONCLUSIONS: It was suggested that the chemical sympathectomy via intraperitoneal injection of guanethidine 50 mg/kg had the therapeutic effect of neuropathic pain in the surgically operated rat which was ligated L5, 6 spinal nerve.