Analgesia In Rats Research Articles

Protracted alcohol abstinence induces analgesia in rats: Possible relationships with BDNF and interleukin-10

Exposure to ethanol alters the expression of brain-derived neurotrophic factor (BDNF) in central regions such as, the hippocampus, cortex and striatum. Moreover, chronic alcohol intake is known to induce selective neuronal damage associated with an increase in the inflammatory cascade, resulting in neuronal apoptosis and neurodegeneration. In the present study, we investigated the nociceptive response after 24h of protracted alcohol abstinence. Rats were submitted to a model of alcohol withdrawal syndrome and the nociceptive response was assessed by the tail-flick and the hot plate tests. In addition, we evaluated BDNF and interleukin-10 (IL-10) in the cerebral prefrontal cortex, brainstem and hippocampus of rats after protracted alcohol abstinence. Male adult Wistar rats were divided into three groups: non-treated group (control group), treated with water (water group), and alcohol (alcohol group). The water and alcohol administrations were done by oral gavage and were performed over three periods of five days of treatment with two intervals of two days between them. Alcohol (20%w/v) was given at 4g/kg of body weight. There was a significant effect of treatment in the tail-flick and hot plate latencies with greater latencies in alcohol-treated rats after 10days of abstinence. There was a significant increase in the prefrontal cortex BDNF levels in the alcohol group in relation to the water group, after 11days of alcohol abstinence. In addition, alcohol withdrawal induced a significant increase in the hippocampus, prefrontal cortex and brainstem IL-10 levels compared with control group. Thus, the present study demonstrates that protracted alcohol withdrawal produced an analgesic effect indexed via increased nociceptive threshold. We suggest that these effects could be related to the increased levels of BDNF and IL-10 observed in the central nervous system.

Hypothalamic paraventricular nucleus stimulation enhances c-Fos expression in spinal and supraspinal structures related to pain modulation

The hypothalamic paraventricular nuclei (PVN) inhibits spinal nociception. Furthermore, projections from the PVN to other structures related to pain modulation exist, but a functional interaction has not yet been fully demonstrated. As an initial approach, we show here that PVN electric stimulation with the same parameters used to induce analgesia in rats enhances c-Fos expression not only in the dorsal horn of the spinal cord but also in the nucleus raphe magnus, locus coeruleus and the periaqueductal gray area. These results suggest that a functional interaction between these structures could occur, possibly to assure a mechanism of endogenous analgesia.

(299) Down-regulation of astroglial glutamate transporters in the locus coeruleus contributes to impairment of endogenous analgesia in rats after peripheral nerve injury

(299) Down-regulation of astroglial glutamate transporters in the locus coeruleus contributes to impairment of endogenous analgesia in rats after peripheral nerve injury

Impairment in Pain Perception in Adult Rats Lesioned as Neonates with 5.7-Dihydroxytryptamine.

Whereas some studies have demonstrated the essential role of 5-hydroxytryptamine (5-HT) in tramadol and acetaminophen analgesia, other research has presented conflicting results. To dispel doubts, some aspects of the involvement of 5-HT in the antinociceptive properties of these drugs remain to be clarified. The aim of this study was to determine whether the serotoninergic system dysfunction produced by neonatal 5-HT lesion in rats may affect the antinociceptive effects of tramadol and acetaminophen administered in adulthood. Three days after birth, the control rats were pretreated with desipramine HCl (20 mg/kg i.p.) 30 min before intraventricular saline--vehicle injection. A separate group received 5.7-DHT; 2×35 µg in each lateral ventricle. At the age of 8 weeks, 5-HT and 5-hydroxyidoleaceticacid (5-HIAA) concentrations were determined in the thalamus and spinal cord by an HPLC/ED method. The antinociceptive effects of tramadol (20 mg/kg i.p.) or acetaminophen (100 mg/kg i.p.) were evaluated by a battery of tests. 5.7-DHT lesioning was associated with a reduction in 5-HT and 5-HIAA content of the thalamus (>85% and >90%) and spinal cord (>58% and 70%). Neonatal 5.7-DHT treatment produced a significant reduction in the antinociceptive effect of tramadol in the hot plate, tail-immersion, paw withdrawal and writhing tests. In the formalin hind paw test, the results were ambiguous. 5-HT lesion was also associated with a decrease in the analgesic effect of acetaminophen in the hot plate and writhing tests. A similar relationship wasn't found in the other assessments conducted with the use of acetaminophen. The present study provides evidence that (1) an intact serotoninergic system is required for the adequate antinociceptive action of tramadol, and (2) the serotoninergic system exerts a negligible influence on acetaminophen-induced analgesia in rats. We hypothesize that similar abnormalities in nociception may occur in patients with 5-HT dysfunction (e.g. depression), so these results should be complied in analgesic dosage adjustment.

Epidural administration of neostigmine-loaded nanofibers provides extended analgesia in rats.

BackgroundIn this study, neostigmine-loaded electrospun nanofibers were prepared and then their efficacy and duration of analgesic action were studied after epidural administration in rats by repeated tail flick and formalin tests.MethodsThe neostigmine poly vinyl alcohol (PVA) nanofibers were fabricated by electrospinning methods. The nanofibers (1 mg) were injected into the lumbar epidural space (L5-L6) of rats (n = 6). Cerebrospinal fluid samples of rats were collected 1, 5 and 24 hours after injection and then were sampled once weekly for 4 weeks. Free-neostigmine concentration was measured in the samples spectrophotometrically. Rat nociceptive responses were evaluated by repeated tail-flick and formalin tests for 5 weeks after the nanofibers (1 mg) injection. Locomotor activity of rats was measured in the open-field at the same period.ResultsThe cerebrospinal fluid concentration of free neostigmine reached 5 μg/ml five hours after injection and remained constant until the end of the experiments. The tail-flick latency of treated rats was significantly (p < 0.01) increased and remained constant up to 4 weeks. Pain scores of the rats in both phases of formalin test were significantly (p < 0.01) reduced during the same periods, Epidural injection of the nanofibers had no effect on locomotor activity of rats in an open-field.ConclusionsOur results indicate that the neostigmine nanofibers can provide sustained release of neostigmine for induction of prolonged analgesia after epidural administration. High tissue distribution and penetration of the nanofibers in dorsal horn can increase thermal and chemical analgesia duration without altering locomotor activity in rats for 4 weeks.

Attenuation of morphine analgesic tolerance by rosuvastatin in naïve and morphine tolerance rats.

Recent studies suggested that statins have anti-inflammatory effects beyond their lipid-lowering properties. Since inflammation in the central nervous system was highly related to morphine tolerance, we sought to investigate whether statins could affect morphine tolerance by mediating glia-derived proinflammatory cytokines secretion. We have undertaken two separate studies: Firstly, we determined the effect of rosuvastatin on naïve rats during induction of morphine tolerance. Secondly, we investigated whether rosuvastation could attenuate the morphine analgesic tolerance in rats that the morphine tolerance established previously. Results demonstrated that peroral rosuvastatin not only delays, but also partially reverses the tolerance to morphine analgesia in rats. The administration of rosuvastatin during induction of morphine tolerance attenuated the activation of ERK and the release of proinflammatory cytokines in the lumbar spinal cord. Similar outcomes were observed in rats were morphine tolerance was established previously. Moreover, our study also found that repeated administration of morphine could activate the astrocytes in the spinal cord while rosuvastation succeeds in suppressing the activation of astrocytes. Our results support the idea that targeting glia-derived proinflammatory effects during morphine treatment is a novel and clinically promising method for enhancing analgesic effects of morphine. We identify a potential new application of statins in the treatment of morphine analgesic tolerance.

P.1.g.091 The endocannabinoid system in the prelimbic cortex mediates fear-conditioned analgesia in rats

P.1.g.091 The endocannabinoid system in the prelimbic cortex mediates fear-conditioned analgesia in rats

The elusive rat model of conditioned placebo analgesia

Recent research on human placebo analgesia has suggested the need for rodent models to further elucidate the neural substrates of the placebo effect. This series of 3 experiments therefore was performed in an attempt to develop a model of placebo analgesia in rats. In each study, female Sprague-Dawley rats received an L5 spinal nerve ligation to induce a neuropathic pain condition. Each rat then underwent a 4-day conditioning procedure in which an active analgesic drug or its vehicle (unconditioned stimulus) was associated with the following cues (conditioned stimuli): novel testing room (environmental), vanilla scent cue (olfactory), dim incandescent lighting (visual), restraint procedure/injection (tactile), and time of day and injection-test latency (temporal). The analgesics for each experiment were as follows: Experiment 1 used 90mg/kg gabapentin, experiment 2 used 3mg/kg loperamide hydrochloride, and experiment 3 used 6mg/kg morphine sulfate. On the following test day, half of the animals received the opposite treatment, resulting in 4 conditioning manipulations: drug/drug, drug/vehicle, vehicle/drug, and vehicle/vehicle. Nociceptive thresholds were assessed with the mechanical paw withdrawal threshold test each day after the conditioning procedure. In all 3 experiments, no significant differences were detected on test day between control and placebo groups, indicating a lack of a conditioned placebo analgesic response. Our results contrast with prior research that implies the existence of a reliable and robust response to placebo treatment. We conclude that placebo analgesia in rats is not particularly robust and that it is difficult to achieve using conventional procedures and proper experimental design.

Dopaminergic modulation of neuropathic pain: analgesia in rats by a D2-type receptor agonist.

Experimental studies have shown that dopaminergic mechanisms can modulate both nociception and chronic pain perception, but such property is not exploited pharmacologically at the clinical level. We have previously shown that levodopa produces D2-receptor-mediated antiallodynic effects in rats with peripheral mononeuropathy. Here, we test the effects of a D2-type receptor (D2R) agonist, quinpirole, on neuropathic pain in rats. Allodynic responses to cooling and light touch were measured in the hind limbs of rats with chronic constriction injury of one sciatic nerve. Single intraperitoneal injection of quinpirole (1 mg/kg) totally inhibited cold and tactile allodynic responses for over 3 and 48 h, respectively. At that dose, quinpirole had no effect on nocifensive responses to heat. Lumbar intrathecal injection of quinpirole produced short-term inhibition of the responses to cold and tactile stimuli, suggesting that spinal mechanisms may contribute to the antiallodynic activity of quinpirole. Chronic subcutaneous infusion of quinpirole by implanted Alzet pumps (0.025 mg/kg·day) provided a slowly progressing inhibition of cold and tactile allodynic responses, which re-emerged after the pumps were removed. These experiments show the involvement of dopaminergic systems in the modulation of chronic allodynias and provide experimental support for proposing the use of D2R agonists for neuropathic pain relief.

Effects of intrathecal carbenoxolone treatment on nociception and analgesia in rat.

Gap junctions (GJ) are important in pain signalling at the spinal cord level. The aim of this investigation was to study the effects of GJ on nociception and the analgesic/hyperalgesic effects of morphine following administration of carbenoxolone as a GJ blocker. Male Wistar rats (200-250 g) were divided into three groups: saline i.p., 10 mg/kg and 1 μg/kg i.p. morphine, each with two subgroups. One was treated intrathecally with saline and the other with carben oxolone. Animal experiment. The thermal nociception threshold was measured prior to and after injections using the tail flick test. Chemical nociception assessment was conducted using a 0.05-mL subplantar injection of 2.5% formalin. Both formalin-induced neurogenic and inflammatory nociception were reduced in the [saline i.p./carbenoxolone i.t.] and [morphine 1 μg/kg, i.p./carbenoxolone i.t.] subgroups (p<0.001). The 10 mg/kg i.p. morphine, i.t./carbenoxolone treatment reduced morphine-induced analgesia in the inflammatory phase (p<0.05), while it was ineffective in the neurogenic phase. Carbenoxolone decreased 1 μg/kg i.p. morphine-induced hyperalgesia in the tail flick test (p<0.001). Based on the results, GJ probably play a role in nociception at the spinal cord level. This may be due to the facilitation of inflammatory mediators released from glial cells or the connection between stimulatory interneurons and projection neurons. GJ blocking attenuated morphine-induced analgesia. This may be due to the attenuation of pre/post-synaptic inhibitory effects of morphine at the spinal cord level. As demonstrated by the investigations, GJ are present between inhibitory interneurons. Therefore, we can assume that blockage of GJ between inhibitory interneurons will reduce morphine-induced analgesia at the spinal cord level. However, this requires further investigation.

Involvement of adrenomedullin in the attenuation of acute morphine-induced analgesia in rats

Adrenomedullin (AM) is a member of calcitonin gene-related peptide (CGRP) family and a pain-related peptide. We have shown that chronic administration of morphine (20μg) upregulates AM activity contributing to morphine tolerance. The present study investigated if AM is involved in acute morphine-induced analgesia. Single intrathecal (i.t.) injection of morphine at a dose of 5μg increased the tail-flick latency (TFL). This analgesic effect was potentiated by the co-administration of the AM receptor antagonist AM22–52 (5 and 10nmol). Exposure of sensory ganglion culture to morphine increased AM content in the ganglia in concentration (0.33–10μM)- and time (10–240min)-dependent manners. However, treatment with morphine (3.3μM) for 30–240min did not alter AM mRNA levels in the cultured ganglia. Furthermore, exposure of ganglion cultures to morphine (3.3μM) for 30–240, but not 10min induced an increase in AM content in the culture medium. These results reveal that a single morphine treatment potentiates post-translational change and the release of AM in sensory ganglia masking morphine-induced analgesia. Thus, targeting AM and its receptors should be considered as a novel approach to improve the analgesic potency of opiates during their acute use.

Analgesic Efficacy and Mode of Action of a Selective Small Molecule Angiotensin II Type 2 Receptor Antagonist in a Rat Model of Prostate Cancer-Induced Bone Pain

The pathobiology of prostate cancer (PCa)-induced bone pain (PCIBP) has both inflammatory and neuropathic components. Previously, we showed that small molecule angiotensin II type 2 receptor (AT2 R) antagonists with >1,000-fold selectivity over the angiotensin II type 1 receptor produced dose-dependent analgesia in a rat model of neuropathic pain. Here, we assessed the analgesic efficacy and mode of action of the AT2 R antagonist, EMA200, in a rat model of PCIBP. At 14-21 days after unilateral intratibial injection of AT3B PCa cells, rats exhibiting hindpaw hypersensitivity received single intravenous bolus doses of EMA200 (0.3-10 mg/kg) or vehicle, and analgesic efficacy was assessed. The mode of action was investigated using immunohistochemical, Western blot, and/or molecular biological methods in lumbar dorsal root ganglia (DRGs) removed from drug-naïve and EMA200-treated PCIBP rats relative to sham-control rats. Intravenous bolus doses of EMA200 produced dose-dependent analgesia in PCIBP rats. Lumbar DRG levels of angiotensin II, nerve growth factor (NGF), tyrosine kinase A (TrkA), phospho-p38 mitogen-activated protein kinase (MAPK), and phospho-p44/p42 MAPK, but not the AT2 R, were increased significantly (P < 0.05) in PCIBP rats, c.f. the corresponding levels for sham controls. EMA200 produced analgesia in PCIBP rats by reducing elevated angiotensin II levels in the lumbar DRGs to attenuate augmented angiotensin II/AT2 R signaling. This in turn reduced augmented NGF/TrkA signaling in the lumbar DRGs. The net result was inhibition of p38 MAPK and p44/p42 MAPK activation. Small molecule AT2 R antagonists are worthy of further investigation as novel analgesics for relief of intractable PCIBP and other pain types where hyperalgesia worsens symptoms.

Experimental evaluation of analgesic activity of PPAR &amp;amp;#947; agonists: pioglitazone and rosiglitazone

Background: To evaluate analgesic activity of pioglitazone and rosiglitazone by tail flick method in rats and acetic acid induced writhing method in mice. Methods: Albino wistar rats of either sex weighing 180-200 g and Swiss mice weighing 25-30 g were used. Study was conducted after approval from the Institutional Animal Ethics Committee. The tail flick method in rats described by D’Amour and Smith (1941) and acetic acid induced writhing in mice were used. The dose of pioglitazone and rosiglitazone were 20 mg/kg and 10 mg/kg respectively. Results: In tail flick method of analgesia, both, pioglitazone and rosiglitazone have analgesic activity which was statistically comparable to aspirin. In acetic acid induced writhing model of analgesia, the action of pioglitazone and rosiglitazone was significantly greater than the control group but it was less when compared to aspirin. Conclusions: Analgesic activity of pioglitazone and rosiglitazone was comparable to aspirin in tail flick model of analgesia in rats while it was significantly less when compared to tramadol. Analgesic activity of pioglitazone and rosiglitazone was significantly less than aspirin in acetic acid induced writhing method.

Central and peripheral relationships between morphine and glucose on antinociception in rats

Previous research from our laboratory has determined that in the absence of a gustatory response or taste hedonics, intraperitoneal (i.p.) glucose administration enhanced morphine-mediated analgesia in rats and had antinociceptive actions on its own. Two experiments examined the potential of a central mechanism for glucose's actions on morphine-mediated antinociception. Morphine (2.5 µg) was infused into the periaqueductal gray (PAG) while glucose (300 mg/kg) was injected into the peritoneal cavity, or glucose (32 nmol) was infused into the PAG while morphine (3.2 mg/kg) was injected i.p. Doses of morphine and glucose were selected based on our own prior research for being below the threshold for analgesic efficacy. Antinociception was assessed using the hot-water tail-withdrawal procedure. Tail-withdrawal latency was tested at baseline (before), and 12, 24 and 36 minutes after the i.p. injection. The results indicated that 300 mg/kg glucose, administered i.p. effectively increased the antinociceptive potency of a low dose of centrally administered morphine, while central infusion of glucose enhanced peripheral morphine-mediated antinociception. These outcomes support previous evidence of glucose's influence on the antinociception actions of opioid drugs. Furthermore, they suggest that glucose produces its enhancing actions on morphine-mediated antinociception in the brain. These results support the hypothesis that glucose does not need to go through a gustatory mechanism or taste hedonics to alter morphine's antinociceptive actions.

Analgesia induced by 2- or 100-Hz electroacupuncture in the rat tail-flick test depends on the anterior pretectal nucleus

AimsThe anterior pretectal nucleus (APtN) and electroacupuncture (EA) activate descending mechanisms to modulate nociceptive inputs in the spinal dorsal horn. This study examines qualitatively whether mechanisms in the APtN participate in the EA-induced analgesia in rats. Main methodsThe tail-flick test was utilized to examine the changes produced by non-selective antagonists of serotonergic (methysergide, 37pg), muscarinic (atropine, 10ng) and opioid (naloxone, 10ng) receptors; selective antagonists against μ (CTOP, 6.4μg), δ (ICI174,864, 6.9μg) or κ (nor-BNI, 7.3μg); 5HT1 (methiothepin, 0.47μg), 5HT2 (ketanserin, 5.4μg), or 5HT3 (MDL 72222, 15.7μg); and GABAA (bicuculline, 150ng) receptors injected into the dorsal (d) or ventral (v) APtN on the antinociception induced by a 20-min EA applied at 2- or 100-Hz frequency to the Zusanli and Sanyinjiao acupoints. Key findingsThe 2-Hz EA-induced analgesia was blocked by naloxone, CTOP or atropine, was less intense after bicuculline, was shorter after methysergide or methiothepin in dAPtN, and was less intense after methysergide, methiothepin and bicuculline in vAPtN. The 100-Hz EA-induced analgesia was less intense after methysergide, methiothepin and CTOP in vAPtN, and remained unchanged after injection of the antagonists into the dAPtN. SignificanceThe 2-Hz EA-induced analgesia utilizes cholinergic muscarinic, μ-opioid, GABAA and 5-HT1 mechanisms in the dAPtN and μ-opioid and 5-HT1 mechanisms in the vAPtN, while 100-Hz EA-induced analgesia utilizes μ-opioid and 5-HT1 mechanisms in the vAPtN but does not utilize them in the dAPtN.

Novel molecular correlates of endocannabinoid‐mediated fear‐conditioned analgesia in rats

Fear-conditioned analgesia (FCA) is the profound suppression of pain during exposure to conditioned aversive stimuli and is mediated at spinal and supraspinal levels. The endocannabinoid system plays a key role in FCA. This study investigated brain and spinal cord expression of genes implicated in pain- and fear-related plasticity (Zif268 and Sgk1), following expression of formalin-evoked nociception, contextual fear or endocannabinoid-mediated FCA. Adult male Lister-Hooded rats received intra-plantar injection of formalin or saline, with or without administration of the CB1 receptor antagonist AM251 (3 mg/kg, i.p.) or vehicle, 30 min prior to re-exposure to an arena paired 24 h previously with footshock. Real time quantitative polymerase chain reaction was used to measure expression of Zif268 and Sgk1 mRNA in the dorsal horn of the spinal cord (DHSC) and rostral ventromedial medulla (RVM) 30 min following arena re-exposure. Intra-plantar injection of formalin resulted in an increase in Zif268 and Sgk1 mRNA expression in the ipsilateral DHSC of non-fear-conditioned rats, effects not observed in rats expressing FCA. Systemic administration of the CB1 receptor antagonist/inverse agonist AM251 attenuated both FCA and the FCA-associated suppression of Zif268 expression in the ipsilateral DHSC without affecting expression of Sgk1. Conditioned fear was associated with an increase in Zif268 mRNA expression in the RVM of saline-, but not formalin-treated rats. The present findings suggest that Zif268 in the DHSC is an important molecular correlate of endocannabinoid-mediated FCA, and that fear-related expression of Zif268 in the RVM is influenced by the presence of nociceptive tone.

Intrathecal neurosteroids and a neurosteroid antagonist: Effects on inflammation-evoked thermal hyperalgesia and tactile allodynia

Neurosteroids regulate neuronal excitability though binding sites associated with the ionotropic γ-aminobutyric acid (GABAA) receptor. We sought to characterize the spinal analgesic actions in rats of two 5α-reduced neurosteroids, allopregnanolone and alphaxalone, on nociceptive processing and to determine whether a putative neurosteroid antagonist attenuates this effect: (3α,5α)-17-phenylandrost-16-en-3-ol (17PA). Intrathecal (IT) injection of allopregnanolone (1–30μg/10μL in 20% cyclodextrin) delivered through lumbar catheters produced a dose-dependent analgesia in rats as measured by thermal thresholds in the ipsilateral (inflamed by intraplantar carrageenan) and in the contralateral (un-inflamed paws). Similar observations were made with alphaxalone (30–60μg in 20% cyclodextrin). Effective doses were not associated with suppressive effects on pinnae, blink or placing and stepping reflex. Effects of allopregnanolone (30μg) on the normal and hyperalgesic paw were completely prevented by IT 17PA (30μg). Reversal by IT 17PA of an equi-analgesic dose of alphaxalone occurred only at higher antagonist dosing. These results suggest that a spinal neurosteroid-binding site with which 17PA interacts may regulate spinal nociceptive processing in normal and inflamed tissue.

Effects of Perineural Administration of Dexmedetomidine in Combination with Levobupivacaine in a Rat Sciatic Nerve Block

ObjectiveThe aim of this study was to assess if perineural administration of dexmedetomidine combined with levobupivacaine increases the duration of the sensory and motor blockade of a sciatic peripheral nerve block in rats. MethodsForty male Sprague–Dawley rats were randomly divided into 5 experimental groups: Group 1, sham; Group 2, perineural levobupivacaine (0.2 mL of a 0.5% solution) and subcutaneous saline; Group 3, perineural levobupivacaine (0.2 mL of a 0.5% solution) plus dexmedetomidine (20 µg/kg dexmedetomidine) and subcutaneous saline; Group 4, perineural saline and subcutaneous dexmedetomidine; and Group 5, perineural saline and subcutaneous saline. Pain reflexes in response to a thermal stimulus were measured at 0 and 240 minutes after drug administration by using a hot-plate and tail-flick tests. Neurobehavioral status, including sensory and motor functions, was assessed by an investigator who was blinded to the experimental groups every 30 minutes until normal functioning resumed. ResultsThe sensory and motor blockades of the rats did not increase in the treatment with dexmedetomidine plus levobupivacaine when compared with the treatment with levobupivacaine alone at all the time points (P > 0.05). Compared with rats in Group 2, those in Group 3 showed significantly higher latency times at 30 and 60 minutes in the hot plate test (P < 0.01). At 30 and 60 minutes, the latency times of the rats in Group 3 were longer than those in Group 2 in the tail-flick test (P < 0.01). Furthermore, the durations of the complete sensory and motor blockade were similar when treatment with levobupivacaine plus dexmedetomidine was compared with treatment with levobupivacaine alone. ConclusionsA 20µg/kg dose of dexmedetomidine added to levobupivacaine did not increase the duration of the sensory and motor blockades in rats. However, treatment with dexmedetomidine plus levobupivacaine increased the quality of analgesia in rats.

Relationship between noradrenaline release in the locus coeruleus and antiallodynic efficacy of analgesics in rats with painful diabetic neuropathy

AimsIn animal models of neuropathic pain, the noradrenergic descending pain inhibitory pathways from the locus coeruleus (LC) may be suppressed. However, no study has investigated the correlation between noradrenaline (NA) release in the LC and efficacy of analgesics in rats with painful diabetic neuropathy. Using microdialysis and analysis of mechanical hypersensitivity, we investigated the correlation between NA release in the LC and efficacy of morphine, tramadol, and clomipramine in rats with diabetic mellitus (DM). Main methodsIn freely moving rats, basal NA concentrations in LC perfusate were quantitated 72 to 96h after microdialysis probe implantation. Following intravenous administration of each drug, NA concentrations were expressed as a percentage of basal values. We concurrently measured the threshold to elicit a paw withdrawal response every 20min for 80min. Key findingsNA concentrations in the LC perfusate were significantly higher in the tramadol and clomipramine groups compared to the morphine group. Naloxone administration did not significantly affect NA concentrations. In the morphine group, NA release in the LC was not significantly correlated with the pain threshold. In contrast, in the tramadol and clomipramine groups, NA release in the LC was significantly correlated with the pain threshold. The correlation coefficient was higher in the clomipramine group than in the tramadol group. SignificanceOur results suggest that the descending noradrenergic pathway can play an important role in analgesia for DM neuropathy and that there is a significant correlation between NA release in the LC and the efficacy of tramadol and clomipramine.

Ausência de efeito antinociceptivo decorrente da administração intravenosa de crotalfina em comparação com morfina, U50-488H ou fenilbutazona em equinos submetidos à estimulação térmica da pele íntegra

Crotalfina é um novo peptídeo analgésico que atua em receptores opioides kappa e delta promovendo potente analgesia em ratos submetidos a modelos de dor inflamatória, neuropática ou oncológica. Talvez a crotalfina possa ser utilizada para tratar a dor em outras espécies. Assim, o objetivo deste estudo foi avaliar a resposta nociceptiva na região escapular e isquiática de cavalos tratados com crotalfina, morfina, U50-488H ou fenilbutazona e submetidos à estimulação térmica na pele íntegra. Dezoito cavalos da raça Puro Sangue Árabe foram alocados em cinco grupos experimentais: GC (5mL NaCl 0,9%), GCRO (3,8mg.kg-1 crotalfina), GK (160 µg.kg-1 U50-488H), GM (0,1mg.kg-1 morfina) e GF (4,4mg.kg-1 fenilbutazona). Os animais foram submetidos ao modelo de dor inflamatória por meio de estimulação térmica (140°C) e durante 24h avaliou-se a latência para o reflexo do frêmito cutâneo na região escapular (LRFCesc) e isquiática (LRFCisq). O U50-488H apresentou efeito antinociceptivo na região isquiática por duas horas, porém, nos demais momentos do grupo GK, bem como nos grupos GC, GCRO, GM e GF, não foi observado efeito antinociceptivo, visto que a LRFCesc e a LRFCisq na pele íntegra de cavalos não aumentaram em 24 horas de avaliação. Portanto, a crotalfina, a morfina, o U50-488H e a fenilbutazona não produziram efeito antinociceptivo relevante em equinos submetidos à estimulação térmica em pele íntegra.