Dynamics of nociceptive sensitivity in rats after melatonin treatment under normal conditions and during long-term stress exposure

Цель - изучение динамики ноцицептивной чувствительности крыс в разные временные периоды после внутрибрюшинного введения мелатонина (10 мг/кг) в условиях нормы и при однократной длительной стрессорной нагрузке на модели 24-ч иммобилизации. Результаты. Установлено, что введение мелатонина приводит к усилению перцептуального компонента ноцицепции животных, выраженность которого возрастает на протяжении 8 сут. наблюдений. На 3-и - 5-е сут. у этих особей выявлено возрастание порога вокализации в ответ на электрокожное раздражение, что иллюстрирует ослабление эмоционального компонента болевой чувствительности. Стрессорное воздействие сопровождалось снижением латентного периода реакции отведения хвоста при светотермальном раздражении, что наблюдалось сразу, а также через 1, 2 и 3 сут. после окончания стрессорного воздействия. В этих условиях увеличение порога вокализации крыс при электрокожной стимуляции обнаружено сразу после стрессорной нагрузки. Указанные изменения характеризуют усиление перцептуального компонента ноцицепции - формирование гипералгезии, но подавление эмоционального восприятия болевого раздражения на ранних стадиях постстрессорного периода. Показано, что экзогенный мелатонин не предупреждает развитие гипералгезии после 24-ч иммобилизации, однако подавляет эмоциональный компонент ноцицептивной чувствительности животных в отдаленный период после длительного стрессорного воздействия (4-е и 7-е сут.). Заключение. Применение мелатонина в целях коррекции измененной болевой чувствительности, при отрицательных эмоциогенных нагрузках, необходимо проводить с учетом временной стадии постстрессорного периода, а также принимая во внимание необходимость воздействия на перцептуальный или эмоциональный компонент ноцицепции. The dynamics of nociceptive sensitivity in rats was studied in various periods after intraperitoneal injection of melatonin (10 mg/kg) under normal conditions and during long-term stress exposure on the model of 24-h immobilization. Administration of melatonin was shown to enhance the perceptual component of nociception, whose degree progressively increased over 8 days of observations. The vocalization threshold of these specimens in response to electrocutaneous stimulation was elevated on days 3-5, which illustrates suppression of the emotional component of nociceptive sensitivity. Stress exposure in animals was accompanied by a decrease in the tail-flick latency during light-heat stimulation. It was observed immediately and 1, 2, and 3 days after termination of the stress procedure. An increase in the vocalization threshold of rats was found immediately after stress. These changes illustrate an enhancement of the perceptual component of nociception (hyperalgesia), but suppression of the emotional evaluation of pain stimulation at the early stage of the post-stress period. Exogenous melatonin did not prevent the development of hyperalgesia after 24-h restraint stress. However, melatonin inhibited the emotional component of nociceptive sensitivity in animals during the late period after long-term stress exposure (days 4 and 7). We conclude that the use of melatonin for correction of changes in nociceptive sensitivity due to negative emotiogenic factors should be performed taking into account the stage of the post-stress period and necessity to affect the perceptual or emotional component of nociception.

Effects of Aging on Current Vocalization Threshold in Mice Measured by a Novel Nociception Assay

Background Age-related changes in nociception have been extensively studied in the past decades. However, it remains unclear whether in addition to the increased incidence of chronic illness, age-related changes in nociception contribute to increased prevalence of pain in the elderly. Although a great deal of evidence suggests that nociception thresholds increase with aging, other studies yield disparate results. The aim of this investigation was to longitudinally determine the effect of aging on nociception. Methods The authors developed a nociception assay for mice using electrical stimuli at 2,000, 250, and 5 Hz that reportedly stimulate Abeta, Adelta, and C sensory nerve fibers, respectively. A system was designed to automate a method that elicits and detects pain-avoiding behavior in mice. Using a Latin square design, the authors measured current vocalization thresholds serially over the course of mice's life span. Results For 2,000-Hz (Abeta), 250-Hz (Adelta), and 5-Hz (C) electrical stimuli, current vocalization thresholds first decreases and then increases with aging following a U-shaped pattern (P < 0.001). In addition, average current vocalization thresholds at youth and senescence are significantly higher than those at middle age for the 250-Hz (Adelta) and 5-Hz (C fiber) electrical stimulus (P < 0.05). Conclusions Using a novel and noninjurious nociception assay, the authors showed that over the life span of mice, current vocalization threshold to electrical stimuli changes in a U-shaped pattern. The findings support the notion that age-related changes in nociception are curvilinear, and to properly study and treat pain, the age of subjects should be considered.

Isobolographic Analysis of Interactions between Intravenous Morphine, Propacetamol, and Diclofenac in Carrageenin-injected Rats

Background It has been suggested that the combination of analgesic drugs may have additive or synergistic effects. In clinical practice, this might allow better analgesia and reduction of side effects. Methods The effects of analgesic drugs were studied in a model of acute inflammatory pain in carrageenin-injected rats using the vocalization threshold to paw pressure. A combination of three different intravenous drugs were used: morphine, diclofenac, and propacetamol, a pro-drug of acetaminophen. The dose-response curves were first obtained for each drug alone. The analgesic potencies of the combinations of morphine and diclofenac (ratios, 1:5.66 and 1:10), morphine and propacetamol (ratio, 1:250), and diclofenac and propacetamol (ratio, 1:65.7) were thereafter evaluated and compared with the effects of the drugs alone. Results For the two different ratios tested, synergy between diclofenac and morphine was observed only with the higher doses. Propacetamol and morphine or diclofenac and propacetamol combinations were additive for all doses tested. Conclusions This study found a synergy between intravenous morphine and diclofenac that is consistent with and helps explain the clinical value of this type of combination in the treatment of acute pain in humans.

Influence of Timing of Administration on the Analgesic Effect of Bupivacaine Infiltration in Carrageenin-injected Rats

Background Recent evidence has suggested that the timing of administration of analgesic drugs could influence their efficacy by reducing the sensitization of the nervous system induced by the nociceptive inputs, but this concept of preemptive analgesia is still debated in both clinical and basic research. Methods The model of acute inflammatory pain induced by carrageenin was used to study the influence of timing of administration of bupivacaine (0.2 ml of a 0.5% solution with 0.005 mg/ml epinephrine) on the development of hyperalgesia, edema, and increase in temperature. The animals received bupivacaine 5 min before (BUPI PRE group, n = 20) or 60 min after (BUPI POST group, n = 20) carrageenin (1 ml/kg of 1% solution) was injected into the left hind paw. Two control groups (n = 15 in each) received saline 5 min before or 60 min after administration of carrageenin. Hyperalgesia of the injected paw was evaluated by the vocalization threshold to paw pressure, edema by measuring paw circumference with a thread, and plantar temperature with a thermocouple thermometer. All measurements were done before carrageenin injection then every 30 min thereafter for 240 min. Another series (n = 24), with the same four groups was also evaluated at 24 h. Results Local injection of bupivacaine 60 min after carrageenin partially reduced the edema and hyperalgesia. The injection of bupivacaine 5 min before carrageenin was more efficient than the delayed injection and reduced hyperalgesia, edema and the increase in temperature temporarily, but did not totally prevent their development. All groups were similar at 240 min and 24 h. Conclusions These results show that a slight advantage of infiltration with bupivacaine before injury exists in this carrageenin model of acute inflammatory pain. However, this benefit is limited in time and bupivacaine did not have any preemptive analgesic effect.