Changes In Nociceptive Thresholds Research Articles

Intravenous Magnesium Sulphate in Standing Horses: Effects on Physiological Parameters, Plasma Concentration of Magnesium and Nociceptive Threshold Tests☆

A bolus of 50 mg kg −1 MgSO4 (treatment Mg) or the same volume of saline (treatment S) was infused over 15 minutes in 5 adult healthy horses. T0 was the end of the infusion. Physiological parameters were recorded throughout the study period. Measurements of electrical, thermal, and mechanical nociceptive thresholds were performed at the pelvic limbs at baseline (before T0), and at specific timepoints. Blood samples were taken at fixed timepoints before, during and until 12 hours after the infusion. For statistical analysis, the 95% confidence intervals (CI's) for the differences in nociceptive thresholds between treatments were calculated. Physiological parameters were compared using a linear mixed model (global α = 0.05, with Bonferroni correction α = 0.0125). The concentrations of ions were also compared with the baseline values at specific timepoints, using a linear mixed model. The Pearson's correlation coefficient was derived between the ion concentrations. The 95% CI's of thermal, mechanical and electrical thresholds were [-1; +2]°C, [0; +3] N and [-1; +1] mA (positive differences indicate higher thresholds for treatment Mg), respectively. Heart rate was significantly higher (P < .0001) and non-invasive systolic arterial pressure (P < .0001) and respiratory rate (P = .0002) significantly lower after treatment Mg compared to treatment S. Additionally, non-invasive systolic arterial pressure was significantly different at T45 (P < .001). Although mild changes in cardiovascular parameters and plasma concentrations were seen with intravenous administration of MgSO4, no changes in nociceptive thresholds were detected in standing non-sedated horses.

Excess abdominal fat is associated with cutaneous allodynia in individuals with migraine: a prospective cohort study

ObjectiveTo investigate the specific relationship between cutaneous allodynia (CA) and the percentages of body fat (BF) and abdominal fat in migraineurs. Additionally, we compared serum levels of inflammatory biomarkers in patients with and without CA.BackgroundExcess abdominal fat might facilitate progressive changes in nociceptive thresholds causing central sensitization, clinically reflected as CA, which could drive migraine progression.MethodsThis prospective cohort study included 80 patients with migraine (mean age 39 years, 81.2% female) and 39 non-migraine controls. We analysed each participant’s height, body weight, and body mass index (BMI). The amount and distribution of BF was also assessed by air displacement plethysmography (ADP) and ViScan, respectively. We analysed serum levels of markers of inflammation, during interictal periods.ResultsWe studied 52 patients with episodic migraine (EM) and 28 with chronic migraine (CM). Of the 80 patients, 53 (53.8%) had CA. Migraineurs with CA had a higher proportion of abdominal fat values than patients without CA (p = 0.04). The independent risk factors for CA were the use of migraine prophylaxis (OR 3.26, 95% CI [1.14 to 9.32]; p = 0.03), proportion of abdominal fat (OR 1.13, 95% CI [1.01 to 1.27]; p = 0.04), and presence of sleep disorders (OR 1.13, 95% CI [00.01 to 1.27]; p = 0.04). The concordance correlation coefficient between the ADP and BMI measurements was 0.51 (0.3681 to 0.6247). CA was not correlated with the mean plasma levels of inflammatory biomarkers.ConclusionsThere is a relation between excess abdominal fat and CA. Abdominal obesity might contribute to the development of central sensitization in migraineurs, leading to migraine chronification.

Behavioural and histological changes in cuprizone-fed mice

Feeding cuprizone (CPZ) to mice causes demyelination and reactive gliosis in the central nervous system (CNS), hallmarks of some neurodegenerative diseases like multiple sclerosis. However, relatively little is known regarding the behavioural deficits associated with CPZ-feeding and much of what is known is contradictory. This study investigated whether 37 days oral feeding of 0.2% CPZ to young adult mice evoked sensorimotor behavioural changes. Behavioural tests included measurements of nociceptive withdrawal reflex responses and locomotor tests. Additionally, these were compared to histological analysis of the relevant CNS regions by analysis of neuronal and glial cell components. CPZ-fed mice exhibited more foot slips in walking ladder and beam tests compared to controls. In contrast, no changes in nociceptive thresholds to thermal or mechanical stimuli occurred between groups. Histological analysis showed demyelination throughout the CNS, which was most prominent in white matter tracts in the cerebrum but was also elevated in areas such as the hippocampus, basal ganglia and diencephalon. Profound demyelination and gliosis was seen in the deep cerebellar nuclei and brain stem regions associated with the vestibular system. However, in the spinal cord changes were minimal. No loss of oligodendrocytes, neurons or motoneurons occurred but a significant increase in astrocyte staining ensued throughout the white matter of the spinal cord. The results suggest that CPZ differentially affects oligodendrocytes throughout the CNS and induces subtle motor changes such as ataxia. This is associated with deficits in CNS regions associated with motor and balance functions such as the cerebellum and brain stem.

Changes in Nociceptive Thresholds and Adenylyl Cyclase System Activity in Skeletal Muscles in Rats with Acute and Mild Type 1 Diabetes

Diabetic peripheral neuropathy (DPN) is one of the commonest complications of type 1 diabetes mellitus (DM1). The aims of the present work were to study the dynamics of the development of pain-type DPN and the functional status of the hormone-sensitive adenylyl cyclase signal system (ACSS) in the skeletal muscle of rats with models of acute and mild DM1 and to investigate the influences on these of insulin therapy using different routes of hormone administration – intranasal and peripheral. The nociceptive threshold in rats decreased in both models of DM1; the stimulatory effects of guanine nucleotides (GIDP) and adrenergic agonists (isoproterenol, BRL-37344) on adenylyl cyclase (AC) also decreased. The AC-stimulating effect of relaxin decreased in animals with acute DM1, while the change in mild DM1 was minor. Peripheral administration of insulin to rats with acute DM1 increased the nociceptive threshold and partially restored the AC effect of the β3 agonist BRL-37344. Intranasal administration of insulin to rats with mild DM1 also led to an increase in the nociceptive threshold and partially restored basal and BRL-37344-stimulated AC activity in the skeletal muscle of diabetic animals. Thus, skeletal muscle in rats with acute and mild DM1 showed impaired nociceptive sensitivity and ACSS function, which was partially restored by treatment of animals with insulin given peripherally (acute DM1) or intranasally (mild DM1).

Long-Term Effects of Chronic Buspirone during Adolescence Reduce the Adverse Influences of Neonatal Inflammatory Pain and Stress on Adaptive Behavior in Adult Male Rats.

Neonatal pain and stress induce long-term changes in pain sensitivity and behavior. Previously we found alterations in pain sensitivity in adolescent rats exposed to early-life adverse events. We tested whether these alterations have long-lasting effects and if those effects can be improved by the 5-hydroxytryptamine 1A (5-HT1A) receptor agonist buspirone injected chronically during the adolescent period. This study investigates: (1) effects of inflammatory pain (the injection of formalin into the pad of a hind paw) or stress (short maternal deprivation-isolation, MI), or their combination in 1–2-day-old rats on the adult basal pain, formalin-induced pain, anxiety and depression; (2) effects of adolescent buspirone in adult rats that experienced similar early-life insults. Changes in nociceptive thresholds were evaluated using the hot plate (HP) and formalin tests; levels of anxiety and depression were assessed with the elevated plus maze and forced swim tests respectively. Both neonatal painful and stressful treatments induced long-term alterations in the forced swim test. Other changes in adult behavioral responses were dependent on the type of neonatal treatment. There was a notable lack of long-term effects of the combination of early inflammatory pain and stress of MI on the pain responses, anxiety levels or on the effects of adolescent buspirone. This study provides the first evidence that chronic injection of buspirone in adolescent rats alters antinociceptive and anxiolytic effects limited to adult rats that showed behavioral alterations induced by early-life adverse treatments. These data highlight the role of 5-HT1A receptors in long-term effects of neonatal inflammatory pain and stress of short MI on adaptive behavior and possibility of correction of the pain and psychoemotional behavior that were altered by adverse pain/stress intervention using buspirone during critical adolescent period.

Ameliorative potential of Alstonia scholaris (Linn.) R. Br. against chronic constriction injury-induced neuropathic pain in rats

BackgroundAlstonia scholaris commonly known as ‘Saptaparni’ is an Indian traditional medicinal plant used in Ayurveda. It is commonly used to treat various disorders like asthma, bronchitis, diarrhea, dysentery and malaria. In folklore medicine the milky juice of the plant is applied on wounds and ulcers to treat pain, ear ache and also in rheumatic pains.AimThe present study was designed to investigate the potential of A. scholaris R. Br. in chronic constriction injury of sciatic nerve (CCI) induced neuropathic pain in rats.MethodsPeripheral neuropathy was induced by chronic constriction injury of sciatic nerve. The behavioral parameters like mechanical and thermal hyperalgesia and cold allodynia were assessed on the 14th day. Tissue parameters like total protein, thiobarbituric acid reactive substances, reduced glutathione, myeloperoxidase, total calcium and TNF-α were assessed to check biochemical changes. Chloroform and methanol extract of A. scholaris leaves (100 and 200 mg/kg) and pregabalin (10 mg/kg, as positive control) were administered orally for 14 consecutive days starting from the day of surgery.ResultsCCI resulted in significant development of mechanical hyperalgesia, heat hyperalgesia and cold allodynia along with alteration in the biochemical changes. Administration of methanol extract at 200 mg/kg significantly attenuated the CCI induced change in nociceptive threshold and biochemical changes which was comparable to that of pregabalin. The high-performance liquid chromatography (HPLC) of the bioactive methanol extract revealed the presence of different types of flavonoids such as gallic acid, catechin, epicatechin, ellagic acid and kaempferol, in which kaempferol was observed to be in higher concentration.ConclusionMethanol extract (200 mg/kg) of A. scholaris showed the ameliorative effect in CCI induced neuropathic pain which may be due to the presence of kaempferol and attributed to its anti-oxidative and anti-inflammatory properties.

Chronic Migraine: An Update on Physiology, Imaging, and the Mechanism of Action of Two Available Pharmacologic Therapies.

Several lines of research support the hypothesis that migraine is a spectrum of illness, with clinical symptoms that vary along a continuum from episodic migraine to chronic migraine. Physiologic changes may result in episodic migraine evolving into chronic migraine over months to years in susceptible individuals. With chronification, headache frequency increases, becoming more disabling and less responsive to therapy. Neurophysiologic and functional imaging research has reported that chronic migraine may be associated with severity‐specific metabolic, functional, and structural abnormalities in the brainstem. Without longitudinal studies, it is unclear whether these changes may represent a continuum of individual progression and/or are reversible. Furthermore, chronic migraine is associated with larger impairments in cortical processing of sensory stimuli when compared with episodic migraine, possibly caused by more pronounced cortical hyperexcitability.Progressive changes in nociceptive thresholds and subsequent central sensitization due to recurrent migraine attacks in vulnerable individuals contribute to the chronic migraine state. This may result in changes to baseline neurologic function between headache attacks, evident in both electrophysiological and functional imaging research. Patients experiencing migraine chronification may report increased non‐headache pain, fatigue, psychiatric disorders (eg, depression, anxiety), gastrointestinal complaints, and other somatic conditions associated with their long‐term experience with migraine pain.Recent research provides a foundation for differentiating episodic and chronic migraine based on neurophysiologic and neuroimaging tools. In this literature review, we consider these findings in the context of models designed to explain the physiology and progression of episodic migraine into chronic migraine, and consider treatment of chronic migraine in susceptible individuals. Advances in pharmacotherapy provide treatment options for chronic migraine. Of the currently available treatment options, only onabotulinumtoxinA and topiramate have received regulatory approval and have demonstrated efficacy in patients with chronic migraine, although the exact mechanisms of action are not fully elucidated.

Application of a handheld Pressure Application Measurement device for the characterisation of mechanical nociceptive thresholds in intact pig tails

The assessment of nociceptive thresholds is employed in animals and humans to evaluate changes in sensitivity potentially arising from tissue damage. Its application on the intact pig tail might represent a suitable method to assess changes in nociceptive thresholds arising from tail injury, such as tail docking or tail biting. The Pressure Application Measurement (PAM) device is used here for the first time on the tail of pigs to determine the reliability of the methods and to provide novel data on mechanical nociceptive thresholds (MNT) associated with four different age groups (9, 17, 24 and 32weeks) and with proximity of the target region to the body of the animal. We recorded an overall acceptable level of intra-individual reliability, with mean values of CV ranging between 30.1 and 32.6%. Across all age groups, the first single measurement of MNT recorded at region 1 (proximal) was significantly higher (P<0.05) than the following two. This was not observed at tail regions 2 and 3 (more distal). Age had a significant effect (P<0.05) on the mean thresholds of nociception with increasing age corresponding to higher thresholds. Furthermore, a significant effect of proximity of tail region to the body was observed (P<0.05), with MNT being higher in the proximal tail region in pigs of 9, 17 and 24weeks of age. There was also a significant positive correlation (P<0.05) between mechanical nociceptive thresholds and age/body size of the animals.To the best of our knowledge, no other investigation of tail nociceptive thresholds has been performed with the PAM device or alternative methods to obtain mechanical nociceptive thresholds in intact tails of pigs of different age/body size. The reliability of the data obtained with the PAM device support its use in the measurement of mechanical nociceptive threshold in pig tails. This methodological approach is possibly suitable for assessing changes in tail stump MNTs after tail injury caused by tail docking and biting.

Paclitaxel-induced increase in NCX activity in subpopulations of nociceptive afferents: A protective mechanism against chemotherapy-induced peripheral neuropathy?

We recently demonstrated, in a rat model of chemotherapy-induced peripheral neuropathy (CIPN), that there is a significant decrease in the duration of the depolarization-evoked Ca2+ transient in isolated somata of putative nociceptive afferents innervating the glabrous skin of the hindpaw, but no change in transient magnitude or the resting concentration of intracellular Ca2+ ([Ca2+]i). Because the Na+-Ca2+ exchanger (NCX) only contributes to the regulation of the duration of the evoked Ca2+ transient, in putative nociceptive dorsal root ganglion (DRG) neurons, we hypothesized that an increase in NCX activity underlies the CIPN-induced change in this subpopulation of neurons. Acutely dissociated retrogradely labeled sensory neurons from naïve, vehicle-, and paclitaxel-treated rats were studied with fura-2 based Ca2+ imaging. There was no difference in the relative level of NCX activity between glabrous neurons from paclitaxel-treated or control rats. However, in contrast to the relatively large and long lasting Ca2+ transients needed to evoke NCX activity in neurons from naïve rats, there was evidence of resting NCX activity in glabrous neurons from both vehicle- and paclitaxel-treated rats. More interestingly, there was a paclitaxel-induced increase in NCX activity in putative nociceptive neurons innervating the thigh, neurons in which there is no evidence of a change in the depolarization-induced Ca2+ transient, or a body site in which there was a change in nociceptive threshold. Furthermore, while the majority of NCX activity in glabrous neurons is sensitive to the NCX3-preferring blocker KB-R7943, the increase in NCX activity in thigh neurons was resistant to KB-R7943 but sensitive to the NCX1-preferring blocker SEA0400. These results suggest that a mechanism(s) other than NCX underlies the paclitaxel-induced decrease in the duration of the evoked Ca2+ transient in putative nociceptive glabrous skin neurons. However, the compensatory response to paclitaxel observed may also explain why only subpopulations of sensory neurons are impacted by paclitaxel, raising the intriguing possibility that CIPN is due to the failure of injured neurons to appropriately compensate for the deleterious consequences of this compound.

Protective effects of phosphatidylcholine on oxaliplatin-induced neuropathy in rats

The present study was designed to investigate the therapeutic potential of phosphatidylcholine (PC) on oxaliplatin-induced peripheral neuropathy. Male Sprague-Dawley rats were randomly divided into three groups: the control group, the oxaliplatin group (4mg/kg, twice per week for 4weeks) and the oxaliplatin+PC (300mg/kg) group. To evaluate the effect of PC, we examined the thermal nociceptive threshold changes in oxaliplatin-induced peripheral neuropathy by conducting paw pressure, hot-plate and tail-flick tests. Additional experiments on the degree of oxidative stress in the sciatic nerves were performed by measuring the level of MDA, total glutathione (GSH), glutathione peroxidase (GPx) activity and superoxide dismutase (SOD) activity. We also used histopathological and immunohistochemical methods to observe neuronal damage and glial activation. PC attenuated oxidative stress by increasing antioxidant levels. In histopathological evaluation, the PC administrated group maintained normal morphologic appearance of sciatic nerves, similar to the control group. In spinal cords, however, no significant difference between the oxaliplatin-alone group and the oxaliplatin+PC group was observed. In the immunohistochemical evaluation, PC administration ameliorated oxaliplatin-induced microglial activation. It is suggested that PC has a therapeutic potential against oxaliplatin-induced peripheral neuropathy due to its antioxidant property and modulation of microglial activities.

Influence of nitric oxide synthase or cyclooxygenase inhibitors on cannabinoids activity in streptozotocin-induced neuropathy

BackgroundInfluence of a relatively specific inhibitor cyclooxygenase (COX)-2, celecoxib, a relatively specific inhibitor of neuronal nitric oxide synthase (NOS), 7-Ni, and a relatively selective inhibitor of inducible NOS, L-NIL, on the action of a preferentially selective CB1 cannabinoid receptor agonist, Met-F-AEA and a selective CB2 cannabinoid receptor agonist, AM 1241 was investigated, in a streptozotocin (STZ)-induced neuropathy. MethodsStudies were performed on male Wistar rats. Changes in nociceptive thresholds were determined using mechanical stimuli – the modification of the classic paw withdrawal test described by Randall-Selitto. Diabetes was induced by a single administration of STZ. ResultsIn a diabetic neuropathic pain model, pretreatment with celecoxib, L-NIL and 7-Ni, significantly increased the antihyperalgesic activity of both Met-F-AEA and AM 1241. ConclusionsThe results of this study seemed to indicate that the interaction between cannabinoid, COX-2 and NOS(s) systems might exist. Concomitant administration of small doses of CB1 and/or CB2 receptor agonists and COX-2 or NOS inhibitors can be effective in the alleviation of diabetic neuropathic pain.

Mechanisms of morphine–venlafaxine interactions in diabetic neuropathic pain model

Backgroundwe investigated the possible mechanisms involved in the interactions of venlafaxine (VFX), a selective serotonin and noradrenaline reuptake inhibitor, and morphine (MRF), an opioid receptor agonist, after acute and chronic VFX treatment in diabetic neuropathic pain model (DNPM). MethodsThe studies were performed on male rats. The changes in nociceptive thresholds were determined by using mechanical stimuli (the Randall–Selitto and the von Frey tests). Diabetes was induced by intramuscular administration of streptozotocin. In order to investigate the mechanism of interaction, animals were also pretreated with naloxone (NLX), a nonselective opioid antagonist, yohimbine (YOH), a nonselective α2-adrenergic antagonist, and p-chloroamphetamine (PCA), a neurotoxin that destroys serotonergic neurons. The μ-opioid receptors’ density was determined with the use of radioligand binding assay. ResultsVFX potentiated antinociceptive action of MRF after acute administration of VFX and this effect was decreased by pretreatment of NLX, YOH and PCA. On the contrary, VFX administered for 21 days prior to MRF significantly decreased the analgesic action of MRF; this effect was augmented only after YOH pretreatment. Also, 21-days administration of VFX caused decreasing tendency in the number of μ-opioid receptors in the brain stem. ConclusionsThe results of our study show that single administration of VFX potentiates antinociceptive action of morphine in DNPM. This effect is probably mediated by both, noradrenergic and serotonergic systems. On the other hand, 21-days administration of VFX significantly decreases analgesic action of MRF. Moreover, there is a possibility that VFX acts as an antagonist of N-methyl-d-aspartate receptors.

Enhancement of antinociceptive effect of morphine by antidepressants in diabetic neuropathic pain model

BackgroundRecent studies have shown that influence of antidepressants on analgesic action of opioids is heterogeneous. The aim of this study was to investigate the effect of acute and repeated (21 days) antidepressant (amitriptyline, moclobemide and reboxetine) treatment on the antinociceptive action of morphine, an opioid agonist, in streptozotocin (STZ)-induced neuropathic pain model. MethodsThe studies were performed on the male Wistar rats. The changes in nociceptive thresholds were determined by using mechanical stimuli (the Randall–Selitto and the von Frey tests). Diabetes was induced by intramuscular administration of STZ. ResultsIn this work we report that acute as well as repeated per os administration of antidepressants (amitriptyline, moclobemide and reboxetine) significantly potentiated the antihyperalgesic effect of morphine in STZ-induced neuropathic pain model. ConclusionCombination therapy, such as classical antidepressants (amitriptyline, moclobemide) with opioids, or agents with noradrenaline reuptake inhibition and μ-opioid receptor activation could be a new target for research into treatment of painful diabetic neuropathy.

Nociceptive Sensitivity and Lymphocytic Index of Peripheral Blood in Rats with Different Behavioral Activity in Model of Infl ammatory Pain Provoked by Injection of Freund’s Complete Adjuvant and Bovine Serum Albumin

Nociceptive thresholds decreased in rats at the early stage of inflammatory reaction induced by subcutaneous injection of BSA and complete Freund's adjuvant. At the later stage of this reaction, there was a trend of restoring nociceptive parameters in behaviorally passive rats in contrast to active animals, which demonstrated further decrease in the nociceptive thresholds. During the late inflammatory period, the lymphocytic index (by Shaganin) changed unidirectionally in the rats with different behavioral parameters. Probably, the changes in nociceptive thresholds were not triggered by the shift in lymphocyte/segmented neutrophil ratio, but resulted from production of yet not established biologically active agents with proalgesic and analgesic nature.

Modification of morphine analgesia by venlafaxine in diabetic neuropathic pain model

BackgroundThe purpose of this study was to investigate the influence of single or chronic (21 days) administration of the serotonin and noradrenaline reuptake inhibitor, venlafaxine, on the antinociceptive action of the opioid receptor agonist, morphine, in streptozotocin (STZ)-induced hyperalgesia. MethodsThe studies were performed on male Wistar rats. Changes in nociceptive thresholds were determined using mechanical stimuli. Diabetes was induced by a single administration of STZ (40mg/kg, im). ResultsVenlafaxine was shown to modulate analgesic activity of morphine in STZ-induced hyperalgesia. However, whereas acute co-administration of venlafaxine increased the analgesic activity of morphine, chronic treatment with venlafaxine attenuated opioid efficacy. ConclusionDepending on the mode of administration (single or long-term), venlafaxine modulates analgesic activity of morphine. Further investigations are necessary to clarify the mechanisms of these interactions, which may be clinically relevant.

Inflammation-induced shift in spinal GABAAsignaling is associated with a tyrosine kinase-dependent increase in GABAAcurrent density in nociceptive afferents

To account for benzodiazepine-induced spinal analgesia observed in association with an inflammation-induced shift in the influence of the GABA(A) receptor antagonist gabazine on nociceptive threshold, the present study was designed to determine whether persistent inflammation is associated with the upregulation of high-affinity GABA(A) receptors in primary afferents. The cell bodies of afferents innervating the glabrous skin of the rat hind paw were retrogradely labeled, acutely dissociated, and studied before and after the induction of persistent inflammation. A time-dependent increase in GABA(A) current density was observed that was more than twofold by 72 h after the initiation of inflammation. This increase in current density included both high- and low-affinity currents and was restricted to neurons in which GABA increased intracellular Ca(2+). No increases in GABA(A) receptor subunit mRNA or protein were detected in whole ganglia. In contrast, the increased current density was completely reversed by 20-min preincubation with the tyrosine kinase inhibitor genistein and partially reversed with the Src kinase inhibitor PP2. Genistein reversal was partially blocked by the dynamin inhibitor peptide P4. Changes in nociceptive threshold following spinal administration of genistein and muscimol to inflamed rats indicated that the pronociceptive actions of muscimol observed in the presence of inflammation were reversed by genistein. These results suggest that persistent changes in relative levels of tyrosine kinase activity following inflammation provide not only a sensitive way to dynamically regulate spinal nociceptive signaling but a viable target for the development of novel therapeutic interventions for the treatment of inflammatory pain.

Effects of Epidural Capsaicin on Nociceptive Threshold and Neurological Functions in Rabbits

Capsaicin, as a principle active component of Chili peppers, is popularly consumed by many people around the world. Whether capsaicin-induced neuropathy alters the function of sensory neurons is still unknown. The objectives of this study were to determine the effects of epidural capsaicin on nociceptive threshold and neurological functions in a rabbit model. An intrathecal injection system was set up using a rabbit model. Rabbits were treated with capsaicin at doses of 0.04, 0.10, and 0.20 mg/kg once. The changes in neurological functions and morphology of the spinal cord and spinal nerve roots were determined within 24 hours. Changes in the nociceptive threshold in the hind limbs of the rabbits were observed for 30 days. Capsaicin's effect on the changing neurological functions was evaluated by the neurological functional scores. The structural changes of spinal cord and spinal nerve roots were observed by hematoxylin and eosin staining and transmission electron microscopy. The nociceptive threshold changes in the rabbits were measured by the responding time for pain induced by a thermostimulation. The results showed that capsaicin reversed changes in the neurological function of rabbit hindlimbs. In the 0.10 and 0.20 mg/kg groups, structural abnormalities were found in the rabbit's spinal nerves. Capsaicin also significantly increased the pain threshold in rabbits when compared with the control group (P < 0.05 or P < 0.01). The maximum values of pain threshold were found in the 0.10 mg/kg capsaicin group after 3 days of capsaicin treatment. With the exception of a potential toxicity, capsaicin may be a potential candidate agent for providing pain relief of both neuropathic and nociceptive conditions.

Randall-Selitto Test: A New Approach for the Detection of Neuropathic Pain after Spinal Cord Injury

In this work we assess the usefulness of the Randall-Selitto test as a method to detect and quantify neuropathic pain responses in rats subjected to different spinal cord injuries. The mechanical nociceptive thresholds were significantly reduced during follow-up after spinal cord contusion or transection. Our results demonstrate that the Randall-Selitto test allows the detection of neuropathic pain both in forepaws and hindpaws, as well as in dorsal and plantar surfaces. Moreover, it does not require weight support capacity, so it can be used at early time points after the injury. This is the first time that this method has been used to describe the changes in nociceptive thresholds that take place after spinal cord injuries of different severities over time.

Endogenous Opioids Released During Non-Nociceptive Environmental Stress Induce Latent Pain Sensitization Via a NMDA-Dependent Process

Although stress induces analgesia, there is evidence that stressful events may exacerbate pain syndromes. Here, we studied the effects of 1 to 3 prestressful events (days 0, 2, and 7), such as non-nociceptive environmental stress, on inflammatory hyperalgesia induced by a carrageenan injection (day 14) in 1 rat hind paw. Changes in nociceptive threshold were evaluated by the paw pressure vocalization test. The higher the number of stress sessions presented to the rats, the greater was the inflammatory hyperalgesia. Blockade of opioid receptors by naltrexone before each stress inhibited stress-induced analgesia and suppressed the exaggerated inflammatory hyperalgesia. Stressed versus nonstressed animals could be discriminated by their response to a fentanyl ultra-low dose (fULD), that produced hyperalgesia or analgesia, respectively. This pharmacological test permitted the prediction of the pain vulnerability level of prestressed rats because fULD analgesic or hyperalgesic indices were positively correlated with inflammatory hyperalgesic indices (r 2 = .84). In prestressed rats, fULD-induced hyperalgesia and the exaggerated inflammatory hyperalgesia were prevented NMDA receptor antagonists. This study provides some preclinical evidence that pain intensity is not only the result of nociceptive input level but is also dependent on the individual history, especially prior life stress events associated with endogenous opioid release. Perspective Based on these preclinical data, it would be of clinical interest to evaluate whether prior stressful events may also affect further pain sensation in humans. Moreover, this preclinical model could be a good tool for evaluating new therapeutic strategies for relieving pain hypersensitivity.

Delayed postoperative latent pain sensitization revealed by the systemic administration of opioid antagonists in mice

The long-lasting post-surgical changes in nociceptive thresholds in mice, indicative of latent pain sensitization, were studied. The contribution of kappa opioid and N-methyl- d-aspartate (NMDA) receptors was assessed by the administration of nor-binaltorphimine or MK-801; dynorphin levels in the spinal cord were also determined. Animals underwent a plantar incision and/or a subcutaneous infusion of remifentanil (80 μg/kg), and mechanical thresholds (von Frey) were evaluated at different times. On day 21, after complete recovery of mechanical thresholds and healing of the wound, one of the following drugs was administered subcutaneously: (−)-naloxone (1 mg/kg), (+)-naloxone (1 mg/kg), naloxone-methiodide (3 mg/kg), or nor-binaltorphimine (5 mg/kg). Another group received subcutaneous MK-801 (0.15 mg/kg) before nor-binaltorphimine administration. Dynorphin on day 21 was determined in the spinal cord by immunoassay. In mice receiving remifentanil during surgery, the administration of (−)-naloxone or nor-binaltorphimine induced significant hyperalgesia even 5 months after manipulation. Nociceptive thresholds remained unaltered after (+)-naloxone or naloxone-methiodide. On day 21 after manipulation, the administration of MK-801 prevented nor-binaltorphimine-induced hyperalgesia. No changes in dynorphin levels were observed before or after opioid antagonist administration. In conclusion, surgery produced latent pain sensitization evidenced by opioid antagonist-precipitated hyperalgesia. The effect was stereospecific, centrally originated, and mediated by kappa opioid receptors. The blockade of nor-binaltorphimine-induced hyperalgesia by MK-801, suggests that NMDA receptors are also involved. Our results show for the first time that surgery induces latent, long-lasting changes in the processing of nociceptive information that can be induced by non-nociceptive stimuli such as the administration of opioid antagonists.