Latency Of Tail-flick Response Research Articles

IS THE MODULATION EFFECT OF MIDAZOLAM ON MORPHINE INDUCED ANTINOCICEPTION TIME DEPENDENT?

Aim: The aim of this study was to investigate the effects of midazolam, morphine and midazolam-morphine on nociception. Benzodiazepines are known to influence opioid analgesia, and variations can be expected in the interaction between benzodiazepines and opioids at different times of the day. Method: The effects of midazolam, morphine, and midazolam-morphine combination on nociception were evaluated with tail flick test in mice, with together the time-dependent changes. Midazolam has not any antinociceptive effect and it inhibited in a fashion dose-dependent the antinociceptive effect of morphine. Results: Control group injected with saline displayed a significant diurnal rhythmicity in the tail flick test significantly. Saline control group’s response latency at light hour (at 16.00 h, P < 0.05) was shorter than that at late dark hour (at 04.00 h) and early morning hour (at 08.00 h). Morphine injected animals had shorter response latencies in light hours (at 12.00 and 16.00 h, P < 0.01) than at late dark hour (at 04.00 h) and early morning hour (at 08.00 h). When midazolam was used in combination with morphine, the tail flick response latencies became significant shorter clearly at every experiment times (P < 0.001), however this inhibition was slightly lower at 04.00 h than the other hours. Conclusion: Our results indicate that midazolam antagonism on morphine antinociception have not diurnal rhythmicity, however it may only slight decreased at late dark hours of day.

A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain

Intervertebral disc (IVD) degeneration is a major cause of low back pain. The transcription factor c-Fos/Activator Protein-1 (AP-1) controls the expression of inflammatory cytokines and matrix metalloproteinases (MMPs) that contribute to the pathogenesis IVD degeneration. We investigated the effects of inhibition of c-Fos/AP-1 on IVD degeneration and associated pain. A selective inhibitor, T-5224, significantly suppressed the interleukin-1β-induced up-regulation of Mmp-3, Mmp-13 and Adamts-5 transcription in human nucleus pulposus cells and in a mouse explant culture model of IVD degeneration. We used a tail disc percutaneous needle puncture method to further assess the effects of oral administration of T-5224 on IVD degeneration. Analysis of disc height, T2-magnetic resonance imaging (MRI) findings, and histology revealed that IVD degeneration was significantly mitigated by T-5224. Further, oral administration of T-5224 ameliorated pain as indicated by the extended tail-flick latency in response to heat stimulation of rats with needle-puncture-induced IVD degeneration. These findings suggest that the inhibition of c-Fos/AP-1 prevents disc degeneration and its associated pain and that T-5224 may serve as a drug for the prevention of IVD degeneration.

Contribution of amygdala CRF neurons to chronic pain

We investigated the role of amygdala corticotropin-releasing factor (CRF) neurons in the perturbations of descending pain inhibition caused by neuropathic pain. Forced swim increased the tail-flick response latency in uninjured mice, a phenomenon known as stress-induced analgesia (SIA) but did not change the tail-flick response latency in mice with neuropathic pain caused by sciatic nerve constriction. Neuropathic pain also increased the expression of CRF in the central amygdala (CeAmy) and ΔFosB in the dorsal horn of the spinal cord. Next, we injected the CeAmy of CRF-cre mice with cre activated AAV-DREADD (Designer Receptors Exclusively Activated by Designer Drugs) vectors. Activation of CRF neurons by DREADD/Gq did not affect the impaired SIA but inhibition of CRF neurons by DREADD/Gi restored SIA and decreased allodynia in mice with neuropathic pain. The possible downstream circuitry involved in the regulation of SIA was investigated by combined injections of retrograde cre-virus (CAV2-cre) into the locus ceruleus (LC) and cre activated AAV-diphtheria toxin (AAV-FLEX-DTX) virus into the CeAmy. The viral injections were followed by a sciatic nerve constriction ipsilateral or contralateral to the injections. Ablation of amygdala projections to the LC on the side of injury but not on the opposite side, completely restored SIA, decreased allodynia and decreased ΔFosB expression in the spinal cord in mice with neuropathic pain. The possible lateralization of SIA impairment to the side of injury was confirmed by an experiment in which unilateral inhibition of the LC decreased SIA even in uninjured mice.The current view in the field of pain research attributes the process of pain chronification to abnormal functioning of descending pain inhibition. Our results demonstrate that the continuous activity of CRF neurons brought about by persistent pain leads to impaired SIA, which is a symptom of dysregulation of descending pain inhibition. Therefore, an over-activation of amygdala CRF neurons is very likely an important contributing factor for pain chronification.

Nociceptive Reactions in Rats during Repeated Stress Exposure.

Changes in nociceptive sensitivity of rats with various behavioral patterns in the open-field test were studied after repeated stress exposure on the model of daily 4-h immobilization for 8 days. The tail-flick latency in response to light-heat stimulation in passive and active specimens decreased most significantly on days 2 and 7, respectively. However, this parameter did not differ from the baseline on day 8 of observations. Vocalization threshold during electrocutaneous stimulation in behaviorally active animals did not change over the first 7 days of repeated stress exposure, but increased significantly on day 8 of the study. The emotional component of nociception in passive animals increased on day 3, but decreased on days 4 and 6 of the experiment. Therefore, repeated stress exposure in rats is mainly accompanied by an increase in the perceptual component of nociception. Variations in the emotional component of nociceptive sensitivity after stress loads are manifested in the initial increase and subsequent decrease in this parameter. The observed changes are more pronounced in behaviorally passive rats than in active animals. These data illustrate the specifics of stress-induced changes in nociception of specimens with various individual and typological characteristics. Our results hold much promise for the development of new individual approaches to modulation of pain sensitivity in humans under conditions of negative emotiogenic exposures.

Comparison of analgesic effect of Huamoyan Keli between two strains of mice

Objective To compare the analgesic effect ofHuamoyan Keli（HMYKL） between Kunming mice and BALB/c mice.Methods Eighty Kunming mice and eighty BALB/c mice were randomly divided into five groups, respectively： a control group, a ibuprofen group, a HMYKL high-dose group（13.98 g crude dru g/kg）, HMYKL middle-dose group（6.99 g crude drug/kg）and a HMYKL low-dose group（3.50 g crude dru g/kg）. There were 16 mice in each group with 8 male mice and 8 female mice. Drugs were administered intragastrically daily for 5 days. After 1 h of drug treatment on day 4, the latency of tail-flick response was evaluated using illuminated pain measurement instrument. After the last drug treatment, pain model was established by i.p. acetic acid, writhing latency and writhing times were recorded to evaluate the analgesic effect of HMYKL.Results In tail-flick test, there was no statistical difference among male and female Kunming mice in the HMYKL groups. Among male BALB/c mice, the latency in HMYKL middle-dose group was significantly longer than that in the control group（4.84±1.16 minvs. 3.93±0.76 min,P〈0.05）. In writhing test, compared with control group（19.06±6.34）, the writhing times among BALB/c mice were decreased in HMYKL high-dose group（8.56±6.19）, HMYKL middle-dose group（5.73±3.17）, HMYKL low-dose group（6.88±4.59）（allP〈0.01）.Conclusion All dose groups of HMYKL showed good analgesic effect on the pain induced by chemical stimulation and there was no sex difference. Kunming mice were not suitable for the evaluation of the analgesic pharmacodynamics because of their large individual difference. On contrast, BALB/c mice which had less individual difference could be used to produce the model of pain. Key words: Humoyan Keli; Analgesics （TCD） ; Pain

Correlation dependencies between nociceptive sensitivity and cytokine level in biological fluids of rats after administration of lipopolysaccharide.

Correlation dependencies between nociceptive sensitivity and cytokine level in biological tissues of rats were studied on days 1 and 7 after antigenic stimulation due to intraperitoneal injection of LPS (30 μg/kg). No correlations were found between the nociceptive thresholds and cytokine contents in the dorsal hippocampus and anterior cingulate cortex of animals. Inverse correlations between the tail-flick latency in response to nociceptive stimulation and concentrations of an anti-inflammatory cytokine IL-10 and pro-inflammatory cytokine TNF-α in the peripheral blood of rats were revealed on day 7 after LPS injection. These animals were characterized by the following inverse correlations between the blood level of proinflammatory cytokines and baseline parameters of nociceptive sensitivity: IL-4 and latency of the tail-flick response; and IL-10 and vocalization threshold. The appearance of significant correlations between immune and nociceptive parameters in rats was shown to coincide with pronounced changes in the perceptual and emotional components of nociception in animals during antigenic stimulation. The formation of close interrelations between nociceptive sensitivity and immune processes in this period probably contributes to the systemic response to antigenic stimulation. Our results complement previous data on the relationship between individual immune reactivity and type of nociceptive reactions in mammals.

Dynamics of changes in nociceptive reactions of rats after peripheral administration of lipopolysaccharide.

The type of changes in nociceptive reactions of rats was studied at various time intervals after intraperitoneal injection of LPS in a dose of 30 μg/kg. The perceptual component of nociception in animals was evaluated from the tail-flick latency in response to light-heat stimulation. The emotional component of nociception in rats was determined from the vocalization threshold during electrocutaneous stimulation of the tail. The tail-flick latency of animals under conditions of light-heat stimulation was shown to decrease 1 day after peripheral administration of LPS, which illustrates an increase in the perceptual component of nociception at the relatively early stage of antigenic stimulation. A significant decrease in the tail-flick latency and vocalization threshold in rats in response to nociceptive stimulation was observed on day 7 after LPS injection. These changes demonstrate an increase in the perceptual and emotional components of nociception at the late period after antigen exposure. Our results indicate that antigenic stimulation due to peripheral administration of LPS is followed by the increase in nociceptive sensitivity of rats. LPS-induced variations in the emotional and perceptual components of nociception in animals suggest the existence of specific mechanisms for systemic regulation of pain. They probably depend on the period of study and type of immune reactions during antigenic stimulation.

In vivo effects of synthetic cannabinoids JWH-018 and JWH-073 and phytocannabinoid Δ9-THC in mice: Inhalation versus intraperitoneal injection

Human users of synthetic cannabinoids (SCBs) JWH-018 and JWH-073 typically smoke these drugs, but preclinical studies usually rely on injection for drug delivery. We used the cannabinoid tetrad and drug discrimination to compare in vivo effects of inhaled drugs with injected doses of these two SCBs, as well as with the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC). Mice inhaled various doses of Δ9-THC, JWH-018 or JWH-073, or were injected intraperitoneally (IP) with these same compounds. Rectal temperature, tail flick latency in response to radiant heat, horizontal bar catalepsy, and suppression of locomotor activity were assessed in each animal. In separate studies, mice were trained to discriminate Δ9-THC (IP) from saline, and tests were performed with inhaled or injected doses of the SCBs. Both SCBs elicited Δ9-THC-like effects across both routes of administration, and effects following inhalation were attenuated by pretreatment with the CB1 antagonist/inverse agonist rimonabant. No cataleptic effects were observed following inhalation, but all compounds induced catalepsy following injection. Injected JWH-018 and JWH-073 fully substituted for Δ9-THC, but substitution was partial (JWH-073) or required relatively higher doses (JWH-018) when drugs were inhaled. These studies demonstrate that the SCBs JWH-018 and JWH-073 elicit dose-dependent, CB1 receptor-mediated Δ9-THC-like effects in mice when delivered via inhalation or via injection. Across these routes of administration, differences in cataleptic effects and, perhaps, discriminative stimulus effects, may implicate the involvement of active metabolites of these compounds.

Analgesic and anti-inflammatory effects of aqueous extract of leaves of Pentatropis capensis Linn. f. (Bullock).

Background:Herbal analgesic and anti-inflammatory remedies are preferred much because of lesser side effects and also a lower tendency for habit formation. Pentatropis capensis is such an analgesic and anti-inflammatory drug which is popular among folklore remedies for various injuries and inflammatory problems. It is called by the name of Kākanāsikā in Ayurvedic works. This study was designed to investigate the analgesic, and anti-inflammatory effects of aqueous extract of P. capensis leaves (AEPC) in rats.Materials and Methods:AEPC was assessed for Analgesic effect through radiant heat tail-flick model and anti-inflammatory effect through carrageenan-induced paw edema model on Wistar strain of albino rats.Results:Pentatropis capensis leaves aqueous extract showed significant (P < 0.001) increase in the duration of latency of tail flick response at the dose levels of 450 mg/kg, p.o. as compared to the control group. Similarly, the similar dose level produced significant (P < 0.01) anti-inflammatory effect against acute paw edema after 3 h of carrageenan induction when compared to the control group.Conclusion:The observed effects were comparable with the standard drug-treated group thus demonstrating effective central analgesic and acute anti-inflammatory potentials of the P. capensis leaves aqueous extract and the observations substantiate its folklore use as an analgesic and anti-inflammatory.

Sucrose-induced analgesia in mice: Role of nitric oxide and opioid receptor-mediated system

Background:The mechanism of action of sweet substance-induced analgesia is thought to involve activation of the endogenous opioid system. The nitric oxide (NO) pathway has a pivotal role in pain modulation of analgesic compounds such as opioids.Objectives:We investigated the role of NO and the opioid receptor-mediated system in the analgesic effect of sucrose ingestion in mice.Materials and Methods:We evaluated the effect of intraperitoneal administration of 10 mg/kg of NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME) and 20 mg/kg of opioid receptor antagonist, naltrexone on the tail flick response in sucrose ingesting mice.Results:Sucrose ingestion for 12 days induced a statistically significant increase in the latency of tail flick response which was unmodified by L-NAME, but partially inhibited by naltrexone administration.Conclusions:Sucrose-induced nociception may be explained by facilitating the release of endogenous opioid peptides. Contrary to some previously studied pain models, the NO/cyclic guanosine monophosphate (cGMP) pathway had no role in thermal hyperalgesia in our study. We recommend further studies on the involvement of NO in other animals and pain models.

Antinociceptive properties of Micrurus lemniscatus venom

The therapeutic potential of snake venoms for pain control has been previously demonstrated. In the present study, the antinociceptive effects of Micrurus lemniscatus venom (MlV) were investigated in experimental models of pain. The antinociceptive activity of MIV was evaluated using the writhing, formalin, and tail flick tests. Mice motor performance was assessed in the rota rod and open field tests. In a screening test for new antinociceptive substances – the writhing test – oral administration of MlV (19.7–1600 μg/kg) produced significant antinociceptive effect. The venom (1600 μg/kg) also inhibited both phases of the formalin test, confirming the antinociceptive activity. The administration of MlV (1600 μg/kg) did not cause motor impairment in the rota rod and open field tests, which excluded possible non-specific muscle relaxant or sedative effects of the venom. The MIV (177–1600 μg/kg) also increases the tail flick latency response, indicating a central antinociceptive effect for the venom. In this test, the MlV-induced antinociceptive effect was long-lasting and higher than that of morphine, an analgesic considered the gold standard. In another set of experiments, the mechanisms involved in the venom-induced antinociception were investigated through the use of pharmacological antagonists. The MlV (1600 μg/kg) antinociceptive effect was prevented by naloxone (5 mg/kg), a non-selective opioid receptor antagonist, suggesting that this effect is mediated by activation of opioid receptors. In addition, the pre-treatment with the μ-opioid receptor antagonist CTOP (1 mg/kg) blocked the venom antinociceptive effect, while the k-opioid receptor antagonist nor-BNI (0.5 mg/kg) or the δ-opioid receptor antagonist naltrindole (3 mg/kg) only partially reduced the venom-induced antinociception. The present study demonstrates, for the first time, that oral administration of M. lemniscatus venom, at doses that did not induce any motor performance alteration, produced potent and long-lasting antinociceptive effect mediated by activation of opioid receptors.

A neuroanatomical correlate of sensorimotor recovery in response to repeated vaginocervical stimulation in rats

Gentle probing against the cervix via the vagina (vaginocervical stimulation, VCS) increases tail flick latency (TFL) to radiant heat; greater force abolishes the tail flick response and other withdrawal responses. This effect occurs in spinal cord-transected rats and in intact rats. On the basis of our earlier finding that VCS releases vasoactive intestinal peptide (VIP) into the spinal cord, and others’ reports of neurotrophic effects of VIP in vitro, we hypothesized that repeated VCS would stimulate sprouting and sensorimotor function of terminals of genital nerve primary afferents in the sacral spinal cord. To test this hypothesis, in the present study, we denervated the genital tract only unilaterally, which significantly reduced the TFL-elevating effect of VCS. Then we applied repeated daily VCS for 1 week and compared the subsequent effectiveness of acute VCS in elevating TFL. The rats that received the repeated daily VCS showed a significantly greater elevation in TFL in response to acute VCS than control rats that did not receive the repeated stimulation. Then, to test whether daily repeated VCS stimulates sprouting of genital primary afferents in such unilaterally genital tract-denervated rats, we transected the contralateral remaining intact pelvic nerve, applied horseradish peroxidase (HRP) to its proximal cut end for 1–2 h, and 2–3 days later counted HRP particles in its terminal zone (L6–S1) in the spinal cord. There were significantly more HRP particles in the rats that received the daily repeated VCS than in the control rats. In the context of these findings, we conclude that VCS in rats can produce a functional sensorimotor recovery via a neurotrophic effect on compromised primary afferents in the spinal cord.

Prevention and Reversal of Morphine Tolerance by the Analgesic Neuroactive Steroid Alphadolone

Alphadolone is a neuroactive steroid that causes antinociception in rats and analgesia in humans by interaction with spinal cord GABA(A) receptors. This study investigated whether alphadolone could affect morphine tolerance. Morphine tolerance was induced in rats with subcutaneous sustained release morphine emulsion (M-SR; 125 mg/kg/day). Tolerance was assessed by a blinded observer using tail flick latency (TFL) response to intraperitoneal (ip) injection of immediate release morphine (M-IR 6.25 mg/kg). Fifty-five rats given M-SR were divided into three groups: group A received 1.0 mL subcutaneous emulsion containing vehicle; groups B and C had emulsions injected subcutaneously at the same time as the M-SR (B-250 mg/kg alphadolone; C-alphaxalone 80 mg/kg). Tail flick latency responses (percentage of maximum possible effect [% MPE]) to M-IR were reduced from 89.6 +/- 2.5 pretreatment to 20.3 +/- 4.8 after M-SR treatment (mean +/- SEM; P < 0.001, one-way anova). Coadministration of alphadolone emulsion with the M-SR caused no sedation and prevented the occurrence of morphine tolerance. TFL responses to M-IR (6.25 mg/kg) given to morphine tolerant rats were 29 +/- 8% MPE whereas the TFL was 78.6 +/- 9.8% MPE when immediate release alphadolone (10 mg/kg ip) was injected at the same time as M-IR to tolerant rats (P < 0.001 one-way anova). Alphaxalone treatment caused sedation and no effects on morphine tolerance. We conclude that the alphadolone can prevent morphine tolerance and it also restores normal morphine antinociception in rats with established morphine tolerance. The lack of sedation suggests clinical utility in human pain states requiring morphine.

COX-2 expression and function in the hyperalgesic response to paw inflammation in mice

Peripheral inflammation and edema are often accompanied by primary and secondary hyperalgesia which are mediated by both peripheral and central mechanisms. The role of cyclooxygenase-2 (COX-2)-mediated prostanoid production in hyperalgesia is a topic of substantial current interest. We have established a murine foot-pad inflammation model in which both pharmacologic and genetic tools can be used to characterize the role of COX-2 in hyperalgesia. Zymosan, an extract from yeast, injected into the plantar surface of the hindpaw induces an edema response and an increase in COX-2 expression in the hindpaw, spinal cord and brain. Zymosan-induced primary hyperalgesia, measured as a decrease in hindpaw withdrawal latency in response to a thermal stimulus, is long-lasting and is not inhibited by pre-treatment with the systemic COX-2 selective inhibitor, parecoxib (20 mg/kg). In contrast, the central component of hyperalgesia, measured as a reduction in tail flick latency in response to heat, is reduced by parecoxib. Zymosan-induced primary hyperalgesia in Cox-2 −/− mice is similar to that of their Cox-2 +/+ littermate controls. However, the central component of hyperalgesia is substantially reduced in Cox-2 −/− versus Cox-2 +/+ mice, and returns to baseline values much more rapidly. Thus pharmacological data suggest, and genetic experiments confirm, (i) that primary hyperalgesia in response to zymosan inflammation in the mouse paw is not mediated by COX-2 function and (ii) that COX-2 function plays a major role in the central component of hyperalgesia in this model of inflammation.

Central Delivery of Dicer-substrate siRNA: A Direct Application for Pain Research

RNA interference (RNAi) is gaining acceptance as a potential therapeutic strategy against peripheral disease, and several clinical trials are already underway with 21-mer small-interfering RNA (siRNA) as the active pharmaceutical agent. However, for central affliction like pain, such innovating therapies are limited but nevertheless crucial to improve pain research and management. We demonstrate here the proof-of-concept of the use of 27-mer Dicer-substrate siRNA (DsiRNA) for silencing targets related to CNS disorders such as pain states. Indeed, low dose DsiRNA (0.005 mg/kg) was highly efficient in reducing the expression of the neurotensin receptor-2 (NTS2, a G-protein-coupled receptor (GPCR) involved in ascending nociception) in rat spinal cord through intrathecal (IT) administration formulated with the cationic lipid i-Fect. Along with specific decrease in NTS2 mRNA and protein, our results show a significant alteration in the analgesic effect of a selective-NTS2 agonist, reaching 93% inhibition up to 3-4 days after administration of DsiRNA. In order to ensure that these findings were not biased by unsuspected off-target effects (OTEs), we also demonstrated that treatment with a second NTS2-specific DsiRNA also reversed NTS2-induced antinociception, and that NTS2-specific 27-mer duplexes did not alter signaling through NTS1, a closely related receptor. Altogether, DsiRNAi represents a potent tool for dissecting nociceptive pathways and could further lead to a new class of central active drugs.

Composition and Antinociceptive Activity of the Essential Oil from Protium Heptaphyllum Resin

The chemical composition of the essential oil from Protium heptaphyllum resin was analyzed by GC/MS and the oil examined for antinociceptive activity in chemical and thermal tests. Fourteen compounds were characterized, representing 95.8% of the total essential oil, with the monoterpenes α-phellandrene (10.4%), α-terpinene (13.7%) and 1,8-cineole (58.7%) as major components. Oral administration of the essential oil (50 and 100 mg/kg) significantly inhibited chemical nociception induced by capsaicin and formalin in mice. In rats, the oil also effectively enhanced the radiant heat-induced tail-flick latency response at a dose of 100 mg/kg. However, the essential oil, at either dose, was ineffective against thermal pain in the hot-plate test.

Role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat

Neurons in the nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, project to medullary nucleus raphe magnus (NRM), which is a key medullary relay for descending pain modulation and is critically involved in opioid-induced analgesia. Previous studies have shown that antinociceptive response of CnF-microinjected morphine can be modulated by the specific subtypes of glutamatergic receptors within the CnF. In this study, we evaluated the role of NMDA and kainate/AMPA receptors that are widely distributed within the NRM on morphine-induced antinociception elicited from the CnF. Hundred and five male Wistar rats weighing 250-300 g were used. Morphine (10, 20 and 40 microg) and NMDA receptor antagonist, MK-801 (10 microg) or kainate/AMPA receptor antagonist, DNQX (0.5 microg) in 0.5 microl saline were stereotaxically microinjected into the CnF and NRM, respectively. The latency of tail-flick response was measured at set intervals (2, 7, 12, 17, 22, 27 min after microinjection) by using an automated tail-flick analgesiometer. The results showed that morphine microinjection into the CnF dose-dependently causes increase in tail-flick latency (TFL). MK-801 microinjected into the NRM, just 1 min before morphine injection into the CnF, significantly attenuated antinociceptive effects of morphine. On the other hand, DNQX microinjected into the NRM, significantly increased TFL after local application of morphine into the CnF. We suggest that morphine related antinociceptive effect elicited from the CnF is mediated, in part, by NMDA receptor at the level of the NRM whereas kainite/AMPA receptor has a net inhibitory influence at the same pathway.

Bis selenide alkene derivatives: A class of potential antioxidant and antinociceptive agents

Bis and tris–selenide alkene derivatives, a class of organoselenium compounds, were screened for antinociceptive and antioxidant activities. In vitro, bis–selenide alkene 1c ( R = 2,4,6-Me 3C 6H 2), 1d ( R = 4-ClC 6H 4) and 1e ( R = 4-MeOC 6H 4) protected against lipid peroxidation about 50%, whereas 1b ( R = C 6H 5) and 1a ( R = C 4H 9) protected only 23%. Compound 1d presented lesser IC 50 against lipid peroxidation than other bis–selenide alkene compounds (1d > 1e ≥ 1c > 1a = 1b). The maximal inhibitory effect of tris–selenide alkenes on lipid peroxidation was in the following order 2c > 2a = 2b. Compound 1e increased the rate of GSH, but not DTT, oxidation. Tris–selenide alkene 2c ( R = 4-MeOC 6H 4) demonstrated the higher rate of thiol oxidation, while 2a ( R = C 6H 5) did not change DTT oxidation but oxidized GSH. Conversely, compound 2b ( R = 4-ClC 6H 4) did not change the rate of GSH oxidation, but oxidized DDT. Bis–selenide alkene derivatives 1c, 1d and 1e were the most promising compounds tested in vitro. In vivo, compounds 1c and 1d (5–50 mg/kg, subcutaneously) produced significant inhibition of acetic acid- and capsaicin-induced pain. Compounds 1c and 1d increased the tail-flick response latency time. The antinociception effect of 1c and 1d was not abolished by naloxone (an antagonist of opioid receptor, 1 mg/kg, subcutaneously), suggesting that the antinociceptive effect is not influenced by the opioidergic mechanism.

Neonatal ethanol exposure produces a hyperalgesia that extends into adolescence, and is associated with increased analgesic and rewarding properties of nicotine in rats.

Drug exposure during CNS development may alter subsequent dependence liability. We postulated that early alcohol exposure might produce persistent alterations in responses to noxious stimuli. Because relief of physical discomfort may be negatively reinforcing, changes in responses to noxious stimuli produced by early alcohol exposure may increase the rewarding properties of nicotine, a potent analgesic. Such factors may contribute to the high level of alcohol and nicotine co-abuse in humans. The purpose of this study was to determine whether neonatal ethanol exposure in rats altered responses to noxious stimuli, and whether nicotine would then be more rewarding to the alcohol-exposed offspring, perhaps via its analgesic actions. Neonatal rats received ethanol by gavage (5.0 or 6.5 g/kg) on postnatal days (PND) 9-13. An iso-caloric control group was also included. Rats were then tested to assess responsiveness to a mild noxious heat stimulus, as measured in the tail-flick assay (PND 14 and PND 28), for their response to acute analgesic injections of either nicotine or ethanol (PND 28), and for nicotine induced conditioned place preference (CPP) (PND 36). Neonatal ethanol exposure produced hyperalgesia during the first 24 h after alcohol withdrawal (PND 14) that continued through PND 28. The analgesic effects of 12.5 microg/kg nicotine were enhanced approximately 2-fold in adolescent rats with previous ethanol histories, relative to controls. These ethanol-exposed rats also showed a significant CPP to nicotine, whereas controls showed no CPP. Persistent decreases in tail-flick response latencies suggestive of hyperalgesia were observed following neonatal ethanol exposure in the rat. These changes were accompanied by increases in the analgesic and place-conditioning effects of nicotine in adolescence. If similar effects occur in humans, prenatal alcohol exposure may play a role in an increased risk for the rewarding effects and dependence liability of nicotine later in life.

The Role of Spinal Opioid Receptors in Antinociceptive Effects Produced by Intrathecal Administration of Hydromorphone and Buprenorphine in the Rat

The intrathecal administration of morphine has been the standard therapy to control long-term intractable pain. Recently, a panel of pain therapy experts suggested that because of the lack of efficacy or because of the side effects produced by morphine in some patients, other drugs, such as hydromorphone and buprenorphine, should be investigated for their analgesic properties. We designed this study to compare the efficacy of intrathecal hydromorphone and buprenorphine to suppress thermal nociception in male Sprague-Dawley rats. An additional objective was to understand whether hydromorphone and buprenorphine bind and act as agonists to μ-, δ-, and κ-spinal opioid receptors. Intrathecally-administered hydromorphone and buprenorphine produced a dose- and time-dependent increase in the tail-flick response latency in rats. The 50% effective dose value for the antinociceptive effect of buprenorphine and hydromorphone were 4 and 69.5 nmol/L, respectively. Both drugs act as agonists to μ-opioid receptors, as determined by their ability to displace [3H]-DAMGO from the spinal opioid receptors and by the ability of an opioid receptor antagonist, naloxone, to reverse their antinociceptive effects. Buprenorphine also has an agonistic effect on the κ-opioid receptors. For the first time, we report that intrathecal buprenorphine is approximately 17 times more effective than hydromorphone in inhibiting thermal pain, and buprenorphine produces its antinociceptive effect by acting as an agonist at both μ- and κ-spinal opioid receptors. Naloxone administered intrathecally was effective in preventing the antinociceptive effects of subsequent intrathecal injections of buprenorphine.