Methylphenidate attenuates signs of evoked neuropathic pain in animal model.

Methylphenidate is a psychostimulant that increases dopamine and noradrenaline levels. Recent studies have shown that methylphenidate potentiates the effect of morphine and together suppress acute and chronic pain. In clinical practice, methylphenidate has been used as a treatment for ADHD and changes of pain threshold have been noted in these patients. The aim of this study was to determine the effect of methylphenidate in an animal model of peripheral neuropathic pain. Neuropathic pain was modeled by the chronic constriction of the sciatic nerve (CCI) in Wistar rats. We evaluated the effect of methylphenidate (1 mg/kg, s.c.) on evoked pain (reflex tests - plantar test, vonFrey test and operant test - thermal place preference) and on spontaneous pain (conditioned place preference). CCI induced thermal, mechanical and cold hyperalgesia/allodynia. Methyphenidate suppressed mechanical and cold hyperalgesia/allodynia, while had no effect on thermal one. Therefore, methylphenidate seems to be a new potential pharmacotherapy for the treatment of neuropathic pain.

Levels of BDNF and NGF in adolescent rat hippocampus neonatally exposed to methamphetamine along with environmental alterations.

Neurotrophins are proteins included in development and functioning of various processed in mammalian organisms. They are important in early development but as well as during adulthood. Brain - derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have been previously linked with many psychiatric disorders such as depression and addiction. Since during postnatal development, brain undergoes various functional and anatomical changes, we included preweaning environment enrichment (EE), since enrichment has been linked with improved function and development of the several brain structure such as hippocampus (HP), in which we monitored these changes. On the other hand, social isolation has been linked with depression and anxiety-like behavior, therefore postweaning social isolation has been added to this model as well and animal were exposed to this condition till adolescence. We examined if all these three factors had impact on BDNF and NGF levels during three phases of adolescence - postnatal days (PDs) 28, 35 and 45. Our results show that EE did not increase BDNF levels neither in control or MA exposed animals and these results are similar for both direct and indirect exposure. On the other side, social separation after weaning did reduce BDNF levels in comparison to standard housing animals but this effect was reversed by direct MA exposure. In terms of NGF, EE environment increased its levels only in indirectly exposed controls and MA animals during late adolescence. On the other hand, social separation increased NGF levels in majority of animals.

Baclofen reversed thermal place preference in rats with chronic constriction injury.

Chronic constriction injury to the sciatic nerve was used as an animal model of neuropathic pain. Instead of frequently used reflex-based tests we used an operant thermal place preference test to evaluate signs of neuropathic pain and the effect of baclofen administration in rats with neuropathy. Chronic constriction injury was induced by four loose ligations of the sciatic nerve. Thermal place preference (45 °C vs. 22 °C and 45 °C vs. 11 °C) was measured after the ligation and after the administration of baclofen in sham and experimental rats. Rats with the chronic constriction injury spent significantly less time on the colder plate compared to sham operated animals at the combination 45 °C vs. 11 °C. After administration of baclofen (10 mg/kg s.c.), the aversion to the colder plate in rats with chronic constriction injury disappeared. At the combination 45 °C vs. 22 °C, no difference in time spent on colder and/or warmer plate was found between sham and experimental animals. These findings show the importance of cold allodynia evaluation in rats with chronic constriction injury and the effectiveness of baclofen in this neuropathic pain model.

The effect of acclimatization and ambient temperature on heat withdrawal threshold in rats.

BACKGROUND: Nociception in rats is frequently measured in terms of latency of withdrawal reaction to radiant heat (thermal nociceptive threshold). The aim of this study was to determine how much housing acclimatization and ambient temperature affect the results of thermal pain threshold testing. METHODS: All experiments used adult male Wistar rats. Thermal pain thresholds were tested using the radiant heat withdrawal reaction at three different body sites: forepaws, hind paws and tail. Skin temperature was measured using an Infrared thermometer and ambient temperature was set at 18, 20, 24 or 26 °C. RESULTS: The results demonstrate that (1) thermal pain threshold was inversely related to both ambient and skin temperature; (2) housing acclimatization and repeated testing had no effect on nociceptive thresholds at any of the three body sites; (3) a resting, cranio-caudal distribution, of nociceptive sensitivity was observed; (4) hind paws and tail were more sensitive to changes of skin and ambient temperature than forepaws. CONCLUSION: These findings show the importance of recording laboratory conditions in experiments and their influence on results.

Pain perception in neurodevelopmental animal models of schizophrenia.

Animal models are important for the investigation of mechanisms and therapeutic approaches in various human diseases, including schizophrenia. Recently, two neurodevelopmental rat models of this psychosis were developed based upon the use of subunit selective N-methyl-D-aspartate receptor agonists--quinolinic acid (QUIN) and N-acetyl-aspartyl-glutamate (NAAG). The aim of this study was to evaluate pain perception in these models. QUIN or NAAG was infused into lateral cerebral ventricles neonatally. In the adulthood, the pain perception was examined. The rats with neonatal brain lesions did not show any significant differences in acute mechanical nociception and in formalin test compared to controls. However, the neonatally lesioned rats exhibited significantly higher pain thresholds in thermal nociception. Increased levels of mechanical hyperalgesia, accompanying the sciatic nerve constriction (neuropathic pain), were also observed in lesioned rats. Although hyperalgesia was more pronounced in QUIN-treated animals, the number of c-Fos-immunoreactive neurons of the lumbar spinal cord was similar in experimental and control rats. We conclude that neonatal brain lesions attenuated the thermal perception in both nociceptive and neuropathic pain whereas mechanical pain was increased in the model of neuropathic pain only. Thus, nociceptive and neuropathic pain belongs--in addition to behavioral changes--among the parameters which are affected in described animal models of schizophrenia.

Prenatal and perinatal factors influencing nociception, addiction and behavior during ontogenetic development.

This review, which summarizes our findings concerning the long-term effects of pre-, peri- and postnatal factors affecting development, nociception and sensorimotor functions, focuses on three areas: 1) perinatal factors influencing nociception in adult rats were examined in rats with hippocampal lesions, after the administration of stress influencing and psychostimulant drugs (dexamethasone, indomethacine and methamphetamine); 2) the effect of pre- and early postnatal methamphetamine administration was shown to impair the development of sensorimotor functions tested in rat pups throughout the preweaning period; 3) the effect of extensive dorsal rhizotomy of the brachial plexus during the early postnatal period was studied with respect to neuropathic pain development and sensorimotor functions. The present study indicates that prenatal or neonatal stress, as well as various drugs, may disturb the development of the nociceptive system and cause long-term behavioral changes persisting to adulthood and that some types of neuropathic pain cannot be induced during the first two postnatal weeks at all. A mature nervous system is required for the development of the described pathological behaviors.

GABA(B) receptor agonist baclofen has non-specific antinociceptive effect in the model of peripheral neuropathy in the rat.

Baclofen, which is a specific agonist of the metabotropic GABA(B) receptor, is used in clinical practice for the treatment of spasticity of skeletal muscles. It also exerts an analgesic effect, but this effect is still not clear and especially controversial in neuropathic pain. In this work, we studied the antinociceptive effects of baclofen in a model of chronic peripheral neuropathic pain - loose ligation of the sciatic nerve (chronic constriction injury, CCI). As controls we used sham-operated animals. The changes of thermal pain threshold were measured using the plantar test 15-25 days after the operation. The obtained results suggest that baclofen increases pain threshold in both groups. The antinociceptive effect of baclofen was dose-dependent and the maximum response without motor deficits was observed at a dose of 15 mg/kg s.c. In the rats with CCI, significant differences between affected (ipsilateral) and contralateral hind paw were present. This difference was dose-dependent, the highest value (6.2+/-1.37 s) was found at the dose of 20 mg/kg. Based on our results and previous findings it could be summarized that baclofen has antinociceptive action, which is attenuated in the model of chronic neuropathic pain probably due to the degeneration of GABA interneurons after chronic constriction injury.

Effects of anesthesia and nociceptive stimulation in an experimental model of brachial plexus avulsion.

Unilateral dorsal rhizotomy of brachial plexus nerves (C5-Th1) performed under general anesthesia is known to induce self-mutilation in rats. The aim of this study was to determine the effect of different anesthetic agents, and of pre-rhizotomy nociceptive stimulation on the appearance of self-mutilation. Self-mutilation appeared in 78% of animals after rhizotomy had been performed under pentobarbital anesthesia. When ketamine was used as the general anesthetic, self-mutilation was almost suppressed (13%) and consisted of superficial erosions. Mechanical nociceptive stimulation, when applied just before the induction of ketamine anesthesia and subsequent rhizotomy, provoked self-mutilation in 91% of rats. Furthermore, a serious type of self-mutilation consisting of total amputation of the distal part of the forepaw was present in 28% of all self-mutilating animals after previous nociceptive stimulation. In terms of self-mutilation, these results suggest 1) the crucial role of anesthesia, especially that which involved NMDA receptors (ketamine), and 2) the need of an additional factor to chronic deafferentation, formed either by activity of nociceptive pathways just before rhizotomy (nociceptive stimulation preceding ketamine anesthesia) or by injury discharges (pentobarbital anesthesia).

Dorsal rhizotomy changes the spontaneous neuronal activity of nuclei in the medial thalamus.

The aim of this study was to examine the influence of unilateral dorsal root section at the cervicothoracic level of the spinal cord on the spontaneous neuronal activity of medial thalamic nuclei in the rat. Single unit extracellular recordings from thalamic nuclei, nc. parafascicularis and nc. centralis lateralis, were obtained with glass micropipettes. The abnormal bursting activity of these nuclei following deafferentation was registered, although a correlation between the occurrence of this activity and the degree of autotomy behavior was not found. Such bursts were never observed in the studied thalamic nuclei of control rats.

[Ethics and legal aspects of use of animals in experimental studies]. / Etické a právní aspekty pouzití zvírat k experimentální práci.

Animals have been used in research since ancient times already. Originally they were used for anatomical and physiological demonstrations. Later they started to be used by another fields--microbiology, toxicology and pharmacology, surgery. Animal use is frequently implicated in relation to ethical problems. Actual view is based on biocentric opinion, which part is formed by "three R's" concept--reduction, replacement, refinement in animal use. Laws applied to animal use in Czech Republic are anchored in Law on Animal Protection and Decree of Ministry of Agriculture on Experimental Animal Use and Breeding. Owing to militant behaviour of organisations involved in animal rights movement there is no adequate propagation of experiments, which are ethically and juridically clear and which particularly help mankind in a struggle against diseases.