Nociceptive Response Latencies Research Articles

A nociceptor-specific RNAi screen in Drosophila larvae identifies RNA-binding proteins that regulate thermal nociception.

Nociception is the process by which sensory neurons detect and encode potentially harmful environmental stimuli to generate behavioral responses. Nociceptor neurons exhibit plasticity in which their sensitivity to noxious stimuli and subsequent ability to drive behavior may be altered by environmental conditions, injury, infection, and inflammation. In some cases, nociceptor sensitization requires regulated changes in gene expression, and recent studies have indicated roles for post-transcriptional mechanisms in regulating these changes as an aspect of nociceptor plasticity. The larvae of Drosophila melanogaster have been developed as a powerful model for studying mechanisms of nociception, nociceptor plasticity, and nociceptor development. Diverse RNA-binding proteins regulate the development and morphology of larval nociceptors, implying important roles for post-transcriptional regulation of gene expression in these neurons, but the importance of these mechanisms for nociceptive behavior has not been investigated systematically. In this study, we conducted a nociceptor-specific RNAi screen of 112 candidate RNA-binding protein genes to identify those that are required for normal sensitivity to noxious thermal stimuli. The screen and subsequent validation experiments identified nine candidate genes (eIF2α, eIF4A, eIF4AIII, eIF4G2, mbl, SC35, snf, Larp4B and CG10445) that produce defects in nociceptive response latency when knocked down in larval nociceptors. Some of the genes identified have well-understood roles in the regulation of translation initiation and regulation of nociceptor sensitization in vertebrate and invertebrate animal models, suggesting an evolutionarily conserved role for these mechanisms in regulating nociceptor sensitivity. Other screen isolates have previously described roles in regulating nociceptor morphology and mRNA processing, but less clear roles in regulating nociceptor function. Further studies will be necessary to identify the mechanisms by which the identified RNA-binding proteins regulate sensory neuron function and the identities of the mRNAs that they target.

The Anti-Nociceptive Potential of Tulathromycin against Chemically and Thermally Induced Pain in Mice.

The present study was conducted to evaluate the analgesic potential of the new triamilide macrolide antibiotic, tulathromycin, at 20 and 40 mg/kg of body weight (BW), subcutaneously against acute pain in mice. Acute pain was induced either chemically (using acetic acid-induced writhing and formalin-induced pain tests) or thermally (using hot-plate, and tail-flick tests). In the acetic acid-induced writhing test, tulathromycin induced a dose-dependent and significant decrease in the number of writhes compared with the control group. In the late phase of the formalin test, a significant decline in hind paw licking time compared with the control group was observed. In the hot-plate and tail-flick tests, tulathromycin caused a dose-dependent and significant prolongation of latency of nociceptive response to heat stimuli, compared with the control group. These findings may indicate that tulathromycin possesses significant peripheral and central analgesic potentials that may be valuable in symptomatic relief of pain, in addition to its well-established antibacterial effect.

The G-protein biased mu-opioid agonist, TRV130, produces reinforcing and antinociceptive effects that are comparable to oxycodone in rats

Mu-opioid agonists (e.g., oxycodone) are highly effective therapeutics for pain. However, they also produce reinforcing effects that increase their likelihood of abuse. Recent strategies in drug development have focused on opioids with biased receptor-signaling profiles that favor activation of specific intracellular pathways over others with the aim of increasing therapeutic selectivity. TRV130, a mu agonist biased towards G-protein signaling, produces antinociceptive effects comparable to the mu agonist, morphine, but exhibits reduced side effects. However, in terms of abuse potential, we know of no published preclinical data investigating the effects of TRV130 as a reinforcer. In the present study, we assessed the relative reinforcing effects of TRV130 and oxycodone, a commonly-prescribed mu agonist, in rats self-administering the drugs under a progressive-ratio (PR) schedule of reinforcement. In addition, we assessed the relative potency and efficacy of TRV130 and oxycodone in rats in a test of thermal antinociception (Hot Plate). For self-administration, male Sprague-Dawley rats (n = 7) self-administered intravenous infusions of TRV130 or oxycodone (0.01-0.32 mg/kg/inj) under a PR schedule of reinforcement. For the Hot-Plate test, male rats (n = 7) received subcutaneous injections of TRV130 (0.1–3.2 mg/kg/inj) or oxycodone (0.1–5.6 mg/kg/inj), and nociceptive response latencies were measured. TRV130 and oxycodone were equi-potent and equi-effective in self-administration and thermal antinociception. This study demonstrates that TRV130 produces reinforcing and antinociceptive effects that are quantitatively similar to oxycodone, and that a biased-signaling profile does not necessarily reduce abuse potential.

Experimental Study of the Analgesic Effect of the Antidepressant Escitalopram.

Antidepressants have been found to possess antinociceptive and analgesic properties and are prescribed in the treatment of chronic pain. To evaluate the antinociceptive properties of escitalopram after a single administration. Forty Wistar rats were used in the study. They were divided into 5 groups (n=8) treated with saline solution (control group), metamizole (150 mg/kg b.w.), escitalopram (5, 10 and 20 mg/kg b.w.) intraperitoneally. The nociceptive tests we used employed thermal (hot plate and plantar test), mechanical (analgesimeter) and chemical (formalin test) stimuli. Criteria for analgesic effect were increased latency in hot plate, plantar test, analgesimeter and decreased paw licking time in formalin test. The reference analgesic metamizole showed significant analgesic effect in all tests excluding the first phase with formalin. Escitalopram in doses of 5 and 20 mg/kg b.w. increased paw withdrawal latency in analgesimeter at 2 hours compared to control. Escitalopram in a dose of 5 mg/kg b.w. increased the duration of the stay on the hot plate at 1 hour, while doses of 10 and 20 mg/kg b.w. significantly increased this indicator at 1 and 3 hours in comparison to the saline treated group. In the plantar test, escitalopram in all used doses significantly increased the nociceptive response latency compared to control. A dose of 5 mg/kg b.w. decreased hind paw licking time during phase 1 of the formalin test, whereas doses of 10 and 20 mg/kg b.w. decreased phase 2 licking time compared to the control group. The antidepressant escitalopram has analgesic properties but they are not dose- or time-dependent.

Phosphatidylcholine attenuated docetaxel-induced peripheral neurotoxicity in rats

Docetaxel is a taxane chemotherapeutic agent used in the treatment of breast cancer, prostate cancer and gastric cancer, but several side effects such as peripheral neurotoxicity could occur. The present study was designed to investigate the therapeutic potential of phosphatidylcholine (PC) on docetaxel-induced peripheral neurotoxicity. Rats were randomly divided into three groups and treated for 4 weeks. Behavioral tests were conducted to measure the effects of PC on docetaxel-induced decreases in mechanical & thermal nociceptive threshold. Biochemical tests were conducted to measure the level of oxidative stress on sciatic nerve. Histopathological and immunohistochemical experiments were also conducted to assess neuronal damage and glial activation. PC treatment significantly attenuated docetaxel-induced changes in mechanical & thermal nociceptive response latencies. PC decreased oxidative stress in sciatic nerve by increasing antioxidant levels (glutathione, glutathione peroxidase and superoxide dismutase activity). In immunohistochemical evaluation, PC treatment ameliorated docetaxel-induced neuronal damage and microglial activation in the sciatic nerve and spinal cord. Thus, PC showed protective effects against docetaxel-induced peripheral neurotoxicity. These effects may be attributed to its antioxidant properties and modulation of microglia.

Pain Perception in Acute Model Mice of Parkinson's Disease Induced by 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)

BackgroundPain is the most prominent non-motor symptom observed in patients with Parkinson’s disease (PD). However, the mechanisms underlying the generation of pain in PD have not been well studied. We used a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD to analyze the relationship between pain sensory abnormalities and the degeneration of dopaminergic neurons.ResultsThe latency to fall off the rotarod and the total distance traveled in round chamber were significantly reduced in MPTP-induced PD mice, consistent with motor dysfunction. MPTP-treated mice also showed remarkably shorter nociceptive response latencies compared to saline-treated mice and the subcutaneous injection of L-3,4-dihydroxyphenylalanine (L-DOPA) partially reversed pain hypersensitivity induced by MPTP treatment. We found that degeneration of cell bodies and fibers in the substantia nigra pars compacta and the striatum of MPTP-treated mice. In addition, astrocytic and microglial activation was seen in the subthalamic nucleus and neuronal activity was significantly increased in the striatum and globus pallidus. However, we did not observe any changes in neurons, astrocytes, and microglia of both the dorsal and ventral horns in the spinal cord after MPTP treatment.ConclusionsThese results suggest that the dopaminergic nigrostriatal pathway may have a role in inhibiting noxious stimuli, and that abnormal inflammatory responses and neural activity in basal ganglia is correlated to pain processing in PD induced by MPTP treatment.

Contribution of sensory C-fiber neuron injury to mechanical dynamic allodynia in a murine model of postherpetic neuralgia

Mechanical dynamic allodynia is a hallmark symptom of postherpetic neuralgia, but the mechanisms are unclear. This study examined the participation of injury to sensory C-fiber and A-fiber neurons in postherpetic dynamic allodynia. Percutaneous inoculation of mice with herpes simplex virus type-1 caused zoster-like skin lesions and dynamic allodynia, which persisted after lesion healed. In postherpetic mice, the intensity of dynamic allodynia was positively and negatively correlated with the withdrawal latency of nociceptive response to heat and the intensity of aversive response to capsaicin, respectively. Calcitonin gene-related peptide immunoreactivity (a C-fiber marker) was markedly reduced, but neurofilament 200 immunoreactivity (an A-fiber neuron marker) was unchanged in the scarred skin of postherpetic mice. In the affected dorsal root ganglion of postherpetic mice, peripherin-immunoreactive (a C-fiber neuron marker) neurons reduced significantly, whereas neurofilament 200-immunoreactive neurons did not. These results suggest that postherpetic dynamic allodynia is associated with injury to sensory C-fiber neurons and little damage to A-fiber neurons.

The evaluation of antinociceptive activity of alkaloid, methanolic, and aqueous extracts of Malaysian Mitragyna speciosa Korth leaves in rats

Mitragyna speciosa Korth is a medicinal plant indigenous to Thailand and Malaysia and has been known for its narcotic and coca-like effects. Many studies have been performed on the antinociceptive effect of the plant extracts of Thai origin; however, limited studies have been reported till date on M. speciosa extracts of Malaysian origin. Various concentrations of alkaloid (5–20 mg/kg), methanolic (50–200 mg/kg), and aqueous (100–400 mg/kg) extracts of Malaysian M. speciosa leaves were prepared and orally administered to nine groups of rats. Morphine (5 mg/kg, s.c.) and aspirin (300 mg/kg, p.o.) were used as control. Antagonism of the antinociceptive activity was evaluated by pretreatment with naloxone at a dose of 2 mg/kg (i.p.). Results showed that oral administration of the alkaloid (20 mg/kg), methanolic (200 mg/kg), and aqueous (400 mg/kg) extracts significantly prolonged the latency of nociceptive response compared with control groups in both hot plate and tail flick tests (P < 0.05). Antinociceptive action of the alkaloid (20 mg/kg), methanolic (200 mg/kg), and aqueous (400 mg/kg) extracts was significantly blocked by naloxone. In conclusion, these results suggest the presence of antinociceptive effect in various extracts of Malaysian M. speciosa leaves. In addition, the antinociceptive effective doses vary depending on the type of solvents used for extraction.

Antinociceptive and anti-inflammatory effects of the ethyl acetate stem bark extract of Bridelia scleroneura (Euphorbiaceae)

Bridelia scleroneura is a member of the Euphorbiaceae family. In folk medicine in Cameroon, the stem bark of this plant is used for relieving abdominal pain, contortion, arthritis and inflammation. In this study, the antinociceptive and anti-inflammatory activities of the ethyl acetate stem bark extract have been evaluated. The putative analgesic effect of the plant extract was examined in abdominal constriction, hot plate, formalin and on pain using tail immersion mouse models and in carrageenan-induced paw edema in rats. The extract (150-600 mg/kg) exhibited a dose-dependent analgesic effect (46.27-78.97%) in acetic acid-induced abdominal constriction in mice. B. scleroneura extract increased the pain latency of nociceptive response to thermal stimuli at the higher dose of 600 mg/kg. B. scleroneuna induced significant dose-dependent reduction of the nociception in both early and late phases of the formalin test. The extract at the dose of 300 mg/kg, increased significantly, by 63.70% and 52.01% the tail-immersion latency time, 1 and 2 h post-dosing. In the carrageenan test, B. scleroneura (150-600 mg/kg, p.o) had dose-dependent and significant effects at different time intervals. This behaviour was similar to indometacin (10 mg/kg) used as a standard drug. These results show that the ethyl acetate stem bark extract of B. scleroneura possesses peripheral and central analgesic properties as well as anti-inflammatory activity against acute inflammation processes, in support of the folk medicinal use of the plant.

A New Assay of Thermal-based Avoidance Test in Freely Moving Mice

The hot plate test is a standard way to measure nociceptive response latencies to a noxious thermal stimulus. Here we have modified the classic hot plate by allowing animals to escape to an adjacent chamber after exposure to the heated surface. In this test, the animals escape to the adjacent chamber after exposure to the hot plate set at 50°C. Repeated exposure to the hot plate resulted in a facilitation of escape responses, as measured by a reduced latency to escape from the noxious thermal stimulus. Signs of nociceptive behavior, such as licking or jumping, were not affected in animals that received hot plate training. The reduction of escape latencies after repeated hot plate exposure might be a useful measure for studying the facilitation of escape responses. In addition, the modified hot plate described here might be useful in studying performance and memory deficits related to noxious thermal stimuli. Perspective We modified a hot plate to measure facilitation of escape responses to a noxious thermal stimulus. The measure of escape responses might be useful in the assessment of memory defects, evaluation of drug therapies, and the behavioral characterization of transgenic mice.

Alterations in the substance P-induced anti-nociception in the central nervous system of rats after morphine tolerance

The present study investigated the alteration in intracerebroventricular administration of substance P-induced anti-nociception after morphine tolerance in rats. The nociceptive response latencies to noxious thermal and mechanical stimulation increased significantly after intracerebroventricular administration of SP in normal rats. The SP-induced anti-nociception decreased significantly in morphine-tolerant rats than that in opioid naïve rats. The results demonstrated that SP induced significant anti-nociceptive effects in the brain in normal rats, and the SP-induced anti-nociception was attenuated significantly in morphine-tolerant rats than that in opioid naïve rats, indicating an alteration in SP-induced anti-nociception in the brain after chronic morphine treatments.

The N-Methyl-D-aspartate Receptor Antagonist Dizocilpine Inhibits Associative Antinociceptive Tolerance to Morphine in Mice: Relation With Memory

I and coauthor previously reported the memory facilitation effect of morphine. The main purpose of this study was to evaluate the involvement of the N-methyl-D-aspartate (NMDA) receptor in associative tolerance to morphine by a contextual procedure. Antinociceptive response latency was measured by the tail-pinch method during repeated morphine (5 mg/kg, s.c.) injection for four consecutive days with pretreatment by dizocilpine (0.01, 0.05, 0.1 mg/kg, i.p.) at 30 min prior to morphine injection in the training phase and before and after morphine injection in the test phase. The nociceptive response latency was shortened by the single administration of dizocilpine (0.05 to 0.25 mg/kg, i.p.). Pretreatment by dizocilpine at 0.05 or 0.1 mg/kg weakened the antinociception to morphine on Day 1, but decreased the tolerance throughout the training phase. In the test phase, the animals were allocated into the same and different contexts. In the test phase, hyperalgesia before morphine injection in the same context and antinociception after morphine injection in the different context were evident in the saline-pretreated group in the training phase, but they were not observed in those contexts in the dizocilpine-pretreated groups. These results suggest that memory dysfunction with dizocilpine inhibits the recovery of associative tolerance to morphine by contextual change.

Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain

The effects of acute, systemic administration of amitriptyline, duloxetine and mirtazapine (antidepressant drugs that variously affect extracellular noradrenaline and serotonin levels) and the selective serotonin reuptake inhibitor (SSRI) citalopram were compared in rat models of experimental pain. None of the drugs (all 3–30 mg/kg, i.p.) affected acute nociceptive responses as measured in the tail flick test. In the hot plate test, duloxetine and mirtazapine significantly increased ( P<0.05) the nociceptive response latency, whereas amitriptyline and citalopram were ineffective. In the formalin test, duloxetine and citalopram significantly attenuated, whereas amitriptyline and mirtazapine increased, second phase flinching behaviour (all P<0.05). However, amitriptyline and mirtazapine reduced second phase licking behaviour. In the chronic constriction injury model of neuropathic pain, thermal hyperalgesia of the injured hindpaw was significantly attenuated by all four drugs ( P<0.05); only amitriptyline and duloxetine fully reversed thermal hypersensitivity. None of the drugs tested attenuated mechanical allodynia. In contrast amitriptyline, duloxetine and mirtazapine significantly reduced mechanical hyperalgesia ( P<0.05); citalopram was ineffective. No drug-related effects on motor performance in the rotarod test were observed. These results (a) highlight the difficulty in correlating antinociceptive effects of drugs from different antidepressant classes across a range of animal pain models and (b) suggest that antidepressants that variously affect both noradrenaline and serotonin levels have more potent and efficacious antinociceptive effects than SSRIs (as exemplified by citalopram), against a range of pain-like behaviours in an animal model of neuropathic pain.

Behavioural effects of the novel AMPA/GluR5 selective receptor antagonist NS1209 after systemic administration in animal models of experimental pain

The effects of systemic administration of the novel AMPA/GluR5 selective receptor antagonist NS1209 in animal models of experimental pain have been tested and compared with the AMPA receptor antagonist NBQX and the opiate morphine. In the mouse hot plate test, NS1209 (3–30 mg/kg, s.c. and i.p.) and morphine (3–30 mg/kg, s.c.) significantly increased the nociceptive response latency, whereas NBQX (3–30 mg/kg, i.p.) was ineffective. In the rat formalin test, a model of persistent pain, NS1209 (3 and 6 mg/kg, i.p.) and morphine (0.5 and 3 mg/kg, s.c.) produced dose-dependent reductions in second phase nociceptive behaviours, although NBQX (10 and 20 mg/kg, i.p.) was without effect. In the chronic constriction injury model of neuropathic pain, NS1209 (3 and 6 mg/kg, i.p.), NBQX (10 and 20 mg/kg, i.p.) and morphine (3 and 6 mg/kg, s.c.) all reduced mechanical allodynia and hyperalgesia responses to von Frey hair and pin prick stimulation of the injured hindpaw. NS1209 and morphine also reduced cold hypersensitivity in response to ethyl chloride stimulation of the injured hindpaw. At the doses associated with anti-nociceptive actions, no effects on motor performance as determined by the rotarod test were observed for any of the drugs tested. Thus, systemic administration of NS1209 at non-ataxic doses has marked analgesic actions comparable to those of morphine in a range of animal models of experimental pain.

Enhanced antinociception by nicotinic receptor agonist epibatidine and adrenal medullary transplants in the spinal subarachnoid space

Adrenal medullary transplants in the spinal subarachnoid space can reduce nociception, via the release of catecholamines and other analgesic substances, and this may be enhanced by stimulation of transplanted chromaffin cell surface nicotinic acetylcholine receptors (nAChRs). In addition, spinal nAChRs have been implicated in modulating nociception and can interact synergistically with α-adrenergic agents. Thus, enhanced antinociception by potent nAChR agonists such as frog skin derivative epibatidine in adrenal-transplanted animals could potentially occur via multiple mechanisms, including nicotinic-α-adrenergic synergy and stimulation of chromaffin cell nicotinic receptors. In order to test this, male Sprague–Dawley rats were implanted with intrathecal catheters and either adrenal medullary or control striated muscle transplants in the spinal subarachnoid space at the lumbar enlargement. Animals were tested for nociceptive responses before and after intrathecal injection of several doses of epibatidine using acute analgesiometric tests (tail flick, paw pressure) and the formalin test. After adrenal medullary, but not control, transplantation, nociceptive thresholds to acute noxious stimuli were slightly but consistently elevated, and phase 2 formalin responses decreased. Following intrathecal injection of epibatidine, acute nociceptive response latencies were modestly elevated and phase 2 formalin flinches modestly suppressed in control animals, but only at the highest dose test, with some attendant motor side-effects. In contrast, in adrenal medullary-transplanted animals, epibatidine elevated responses to acute noxious stimuli and markedly suppressed phase 2 formalin responses in a dose-related fashion. The enhanced antinociceptive effect following epibatidine was attenuated with either nAChR antagonist mecamylamine or α-adrenergic receptor antagonist phentolamine. The current results demonstrate that intrathecal injection of the nAChR ligand epibatidine can produce significant antinociception in adrenal-transplanted rats in both acute and tonic nociceptive tests and suggest that the use of nicotinic agents in combination with adrenal medullary transplantation could provide maximal therapeutic benefit by synergistically improving antinociception while avoiding the detrimental side-effects of these agents.

Involvement of endogenous beta-endorphin in antinociception in the arcuate nucleus of hypothalamus in rats with inflammation

Although exogenous administration of beta-endorphin to the arcuate nucleus of hypothalamus (ARC) had been shown to produce antinociception, the role of endogenous beta-endorphin of the ARC in nociceptive processing has not been studied directly. The aim of the present study was to investigate the effect of endogenous beta-endorphin in the ARC on nociception in rats with carrageenan-induced inflammation. The hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation was assessed by the hot-plate test and the Randall Selitto Test. Intra-ARC injection of naloxone had no significant influence on the HWL to thermal and mechanical stimulation in intact rats. The HWL decreased significantly after intra-ARC injection of 1 or 10 μg of naloxone in rats with inflammation, but not with 0.1 μg of naloxone. Furthermore, intra-ARC administration of the selective mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA) decreased the nociceptive response latencies to both stimulation in a dose-dependent manner in rats with inflammation, while intra-ARC administration of the selective delta-opioid receptor antagonist naltrindole or the selective kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) showed no influences on the nociceptive response latency. The antiserum against beta-endorphin, administered to the ARC, also dose-dependently reduced the HWL in rats with inflammation. The results indicate that endogenous beta-endorphin in the ARC plays an important role in the endogenous antinociceptive system in rats with inflammation, and that its effect is predominantly mediated by the mu-opioid receptor.

Involvement of neuropeptide Y and Y1 receptor in antinociception in nucleus raphe magnus of rats

The nociceptive response latencies increased significantly after intra-nucleus raphe magnus administration of 0.1 or 0.4 nmol of neuropeptide Y, but not 0.04 nmol, in rats. The neuropeptide Y-induced increases in hindpaw withdrawal latency were reversed by following injection of 0.42 nmol of the Y1 antagonist, NPY(28–36). The results indicate that NPY plays an antinociceptive role in nucleus raphe magnus in rats, which is mediated by the Y1 receptor. Furthermore, the neuropeptide Y-induced increases in hindpaw withdrawal latency were attenuated by following intra-nucleus raphe magnus injection of 6 nmol of the opioid antagonist naloxone, indicating that there is an interaction between NPY and opioids in nucleus raphe magnus.

Intra-periaqueductal grey injection of galanin increases the nociceptive response latency in rats, an effect reversed by naloxone

The nociceptive response latencies were increased significantly after intra-periaqueductal grey (PAG) administration of 1.0 or 3.0 nmol of galanin, but not 0.3 nmol, in rats. The effect of galanin was attenuated by following injection of 5.5 nmol of naloxone into PAG. These results indicate an anti-nociceptive role of galanin, and a possible interaction between galanin and opioid peptides in PAG in rats.

Effect of capsaicin on learning, retention and extinction of spatial and active avoidance tasks in adult rats neonatally treated

The relationship between learning capability and neurological damage following neonatal treatment with capsaicin (50 mg/kg) was studied in adult Wistar rats of either sex using different experimental procedures. First of all, the reaction to a stress-inducing situation was evaluated by analysing the behavior of capsaicin and vehicle-treated rats in an open field situation. No differences were observed between these two groups. Moreover, the parameters considered were similar to those of untreated, age-matched animals. Rats treated with capsaicin showed a marked learning impairment of an appetitive task in a complex maze. On the contrary, no alterations were observed in both retention and extinction of this conditioned behavior. In spatial discrimination investigated using a different maze (8-arm radial maze) but with the same reinforcement (food), no difference was found between capsaicin-and vehicle-treated rats. In both groups a trial number-related increase of the responding efficiency and a decrease in the mean running time were observed. Neonatally treated rats behaved also similarly in aversive conditioning. However, their learning performances were much better than those of untreated rats. These results confirm that neonatal exposure to painful stimuli later improves active avoidance performance. Capsaicin treatment did not have any effect on the latency of nociceptive response in the hot-plate test.

The Antinociceptive Effect of S-(+)-Ibuprofen in Rabbits

This study was designed to determine whether systemic absorption plays any role in the antinociceptive effect of epidural (EP) sodium S(+)-ibuprofen (IB). One week after surgical implantation of EP catheters, six rabbits were given EP injections with either normal saline (NS) 0.4 mL or IB 10 mg in 0.4 mL NS (Group 1) on separate days. Each animal was injected with IB 10 mg intravenously (i.v.) on another day. Six control rabbits (Group 2) had neither surgery nor any injection. Analgesic testing was performed using electric stimulation through two electrocardiogram (ECG) skin electrodes with built-in adhesive, attached to shaved hip areas using 50 V, 1 Hz, 3 ms, before and 0.5,1,2 and 3 h after injection in Group 1, and in similar times in controls. The 95% confidence intervals (CI) of the mean difference between baseline and maximal nociceptive response latency of all groups were compared using analysis of covariance (ANCOVA) adjusted for baseline measurements. This comparison covered all possible pairs among all groups. Significant antinociceptive effects were seen after EP IB but not after control or i.v. IB. Neither motor dysfunction nor evidence of systemic toxicity or neurotoxicity was observed in any animal.