Increase In Tail-flick Latency Research Articles

Anti-analgesia and reduced antinociception from supraspinally administered β-endorphin in stressed rats: dependence on spinal cholecystokinin via cholecystokinin B receptors

Rats exposed to the stress of repeated exposure to a noxious heat source (52.5°C, hot plate) exhibit stress-induced analgesia, but reduced antinociception (detected using the tail-flick test) to the administration of β-endorphin into the periaqueductal gray region of the brain. This is accompanied by an anti-analgesic response (reduction in the stress-induced increase of tail flick latency) to doses of β-endorphin (0.03 nmol) lower than those usually associated with antinociception. These alterations are prevented and antinociceptive potency is maintained when rats are treated with cholecystokinin (CCK) antagonists intrathecally. The potency of L-365,260 and L-364,718, selective CCK B and CCK A receptor antagonists, respectively, correlated with their apparent affinities for CCK B receptors, suggesting that the altered sensitivity to β-endorphin is mediated via CCK B receptors.

Brain renin angiotensin system (RAS) in stress-induced analgesia and impaired retention

Physiological stress is known to produce analgesia and memory disruption. Brain renin angiotensin system (RAS) has been reported to participate in stress response and plays a role in the processing of sensory information. Angiotensin receptors (AT), particularly AT 1 subtypes have been reported to be distributed in brain areas that are intimately associated with stress response. The purpose of present study was to examine the modulation of AT 1 receptor in the immobilization stress and angiotensin II (AngII)-induced analgesia and impaired retention, and to determine whether resultant behavioral changes involve common sensory signals. Result of present experiments showed that immobilization stress in mice and rats, and intracerebroventricular (ICV) administration of AngII (10 and 20 ng) in rats produced an increase in tail-flick latency. Similarly, post training administration of AngII or immobilization stress produced impairment of retention tested on plus-maze learning and on passive avoidance step-down task. Both these responses were sensitive to reversal by prior treatment with losartan (10 and 20 mg/kg), an AT 1 AngII receptor antagonist. On the other hand, naloxone, an opiate antagonist preferentially attenuated the stress and AngII-induced analgesia and retention deficit induced by immobilization stress, but failed to reverse the AngII induced retention deficit. These results suggest immobilization stress-induced analgesia and impaired retention involves the participation of brain RAS. Further, failure of naloxone to reverse AngII-induced retention impairment shows, AngII-induced behavioral changes are under control of different sensory inputs.

The effects of serotonin biosynthesis inhibition on nicotine and nifedipine-induced analgesia in rats.

The calcium channel blocker nifedipine has analgesic properties that are enhanced by nicotine. Although it is not known how this analgesic state might affect the awareness of anginal pain and impending myocardial infraction, recent studies have shown an increased mortality associated with the use of large doses of nifedipine. Because both nifedipine- and nicotine-induced analgesia involve serotonergic mechanisms, we studied the effects of the serotonin biosynthesis inhibitor parachlorophenylalanine (pCPA) on nifedipine- and nicotine-induced analgesia. Nociception was assessed by tail-flick method. Rats pretreated with pCPA (300 mg/kg intraperitoneally [IP]) followed by either nifedipine (15 mg/kg IP) or nicotine (1 mg/kg subcutaneously) had a increase in tail-flick latency of 41% (P = 0.09) and 50% (P = 0.05), respectively, compared with animals that did not receive pCPA. Additionally, rats pretreated with pCPA followed by a combination of nicotine and nifedipine doubled their tail-flick latency (P = 0.0001) compared with animals that were not treated with pCPA. These data further support the involvement of the serotonergic system in both nifedipine- and nicotine-induced analgesia and suggest that drugs that affect serotonin levels, including tricyclic antidepressants and serotonin-specific reuptake inhibitors, may also affect the analgesia induced by nifedipine and nicotine. This study examines the effect of serotonin depletion on nicotine- and nifedipine-induced analgesia. Nifidipine is a calcium channel blocker used to treat high blood pressure. It also has pain-relieving properties that are enhanced by nicotine. Because both nifedipine- and nicotine-induced analgesia involve the neurotransmitter serotonin, it is important to know how changes in serotonin concentration might affect both nicotine- and nifedipine-induced analgesia. This study not only supports the involvement of the serotonergic system in both nifidipine- and nicotine-induced analgesia, but also suggests that drugs that affect serotonin levels may also affect analgesia induced by nifidipine and nicotine.

The Effects of Serotonin Biosynthesis Inhibition on Nicotine and Nifedipine-Induced Analgesia in Rats

The calcium channel blocker nifedipine has analgesic properties that are enhanced by nicotine.Although it is not known how this analgesic state might affect the awareness of anginal pain and impending myocardial infraction, recent studies have shown an increased mortality associated with the use of large doses of nifedipine. Because both nifedipine- and nicotine-induced analgesia involve serotonergic mechanisms, we studied the effects of the serotonin biosynthesis inhibitor parachlorophenylalanine (pCPA) on nifedipine- and nicotine-induced analgesia. Nociception was assessed by tail-flick method. Rats pretreated with pCPA (300 mg/kg intraperitoneally [IP]) followed by either nifedipine (15 mg/kg IP) or nicotine (1 mg/kg subctaneously) had a increase in tail-flick latency of 41% (P = 0.09) and 50% (P = 0.05), respectively, compared with animals that did not receive pCPA. Additionally, rats pretreated with pCPA followed by a combination of nicotine and nifedipine doubled their tail-flick latency (P = 0.0001) compared with animals that were not treated with pCPA. These data further support the involvement of the serotonergic system in both nifedipine- and nicotine-induced analgesia and suggest that drugs that affect serotonin levels, including tricyclic antidepressants and serotonin-specific reuptake inhibitors, may also affect the analgesia induced by nifedipine and nicotine. Implications: This study examines the effect of serotonin depletion on nicotine- and nifedipine-induced analgesia. Nifidipine is a calcium channel blocker used to treat high blood pressure. It also has pain-relieving properties that are enhanced by nicotine. Because both nifedipine- and nicotine-induced analgesia involve the neurotransmitter serotonin, it is important to know how changes in serotonin concentration might affect both nicotine- and nifedipine-induced analgesia. This study not only supports the involvement of the serotonergic system in both nifidipine- and nicotine-induced analgesia, but also suggests that drugs that affect serotonin levels may also affect analgesia induced by nifidipine and nicotine. (Anesth Analg 1998;87:1109-12)

Attenuation of tolerance to opioid-induced antinociception and protection against morphine-induced decrease of neurofilament proteins by idazoxan and other I2-imidazoline ligands.

1. Agmatine, the proposed endogenous ligand for imidazoline receptors, has been shown to attenuate tolerance to morphine-induced antinociception (Kolesnikov el al., 1996). The main aim of this study was to assess if idazoxan, an alpha2-adrenoceptor antagonist that also interacts with imidazoline receptors, could also modulate opioid tolerance in rats and to establish which type of imidazoline receptors (or other receptors) are involved. 2. Antinociceptive responses to opioid drugs were determined by the tail-flick test. The acute administration of morphine (10 mg kg(-1), i.p., 30 min) or pentazocine (10 mg kg(-1), i.p., 30 min) resulted in marked increases in tail-flick latencies (TFLs). As expected, the initial antinociceptive response to the opiates was lost after chronic (13 days) treatment (tolerance). When idazoxan (10 mg kg(-1), i.p.) was given chronically 30 min before the opiates it completely prevented morphine tolerance and markedly attenuated tolerance to pentazocine (TFLs increased by 71-143% at day 13). Idazoxan alone did not modify TFLs. 3. The concurrent chronic administration (10 mg kg(-1), i.p., 13 days) of 2-BFI, LSL 60101, and LSL 61122 (valldemossine), selective and potent I2-imidazoline receptor ligands, and morphine (10 mg kg(-1), i.p.), also prevented or attenuated morphine tolerance (TFLs increased by 64 172% at day 13). This attenuation of morphine tolerance was still apparent six days after discontinuation of the chronic treatment with LSL 60101-morphine. The acute treatment with these drugs did not potentiate morphine-induced antinociception. These drugs alone did not modify TFLs. Together, these results indicated the specific involvement of I2-imidazoline receptors in the modulation of opioid tolerance. 4. The concurrent chronic (13 days) administration of RX821002 (10 mg kg(-1), i.p.) and RS-15385-197 (1 mg kg(-1), i.p.), selective alpha2-adrenoceptor antagonists, and morphine (10 mg kg(-1), i.p.), did not attenuate morphine tolerance. Similarly, the concurrent chronic treatment of moxonidine (1 mg kg(-1), i.p.), a mixed I(1)-imidazoline receptor and alpha2-adrenoceptor agonist, and morphine (10 mg kg(-1), i.p.), did not alter the development of tolerance to the opiate. These results discounted the involvement of alpha2-adrenoceptors and I(1)-imidazoline receptors in the modulatory effect of idazoxan on opioid tolerance. 5. Idazoxan and other imidazol(ine) drugs fully inhibited [3H]-(+)-MK-801 binding to N-methyl-D-aspartate (NMDA) receptors in the rat cerebral cortex with low potencies (Ki: 37-190 microM). The potencies of the imidazolines idazoxan, RX821002 and moxonidine were similar, indicating a lack of relationship between potency on NMDA receptors and ability to attenuate opioid tolerance. These results suggested that modulation of opioid tolerance by idazoxan is not related to NMDA receptors blockade. 6. Chronic treatment (13 days) with morphine (10 mg kg(-1), i.p.) was associated with a marked decrease (49%) in immunolabelled neurofilament proteins (NF-L) in the frontal cortex of morphine-tolerant rats, suggesting the induction of neuronal damage. Chronic treatment (13 days) with idazoxan (10 mg kg(-1)) and LSL 60101 (10 mg kg(-1)) did not modify the levels of NF-L proteins in brain. Interestingly, the concurrent chronic treatment (13 days) of idazoxan or LSL 60101 and morphine, completely reversed the morphine-induced decrease in NF-L immunoreactivity, suggesting a neuroprotective role for these drugs. 7. Together, the results indicate that chronic treatment with I2-imidazoline ligands attenuates the development of tolerance to opiate drugs and may induce neuroprotective effects on chronic opiate treatment. Moreover, these findings offer the I2-imidazoline ligands as promising therapeutic coadjuvants in the management of chronic pain with opiate drugs.

Intrathecal methysergide antagonizes the antinociception, but not the hyperalgesia produced by microinjection of baclofen in the ventromedial medulla of the rat

Microinjection of baclofen, a γ-aminobutyric acid B (GABA B) receptor agonist, in the nucleus raphe magnus (NRM) or nucleus reticularis gigantocellularis pars α (NGCp α) of the rat produces antinociception at doses of 0.1–1.0 ng and hyperalgesia at doses of 30–150 ng in the tail-flick test. The antinociception is proposed to result from disinhibition of spinally-projecting neurons in this region that contain serotonin. The hyperalgesia is proposed to result either from inhibition of these neurons or from disinhibition of a serotonergic pain facilitatory pathway that also originates in this area of the ventromedial medulla. To determine the involvement of bulbospinal serotonergic pathways in the biphasic effects of baclofen, rats were pretreated intrathecally with either 30 μg of methysergide or saline. Ten minutes later, either saline, 0.5 ng or 150 ng of baclofen was microinjected in the NRM and NGCp α, and alterations in nociceptive threshold were assessed by the tail-flick and hot-plate tests. Intrathecal pretreatment with methysergide prevented the increase in tail-flick latency produced by 0.5 ng of baclofen, but did not prevent the decrease in tail-flick latency produced by 150 ng of baclofen. Neither dose of baclofen altered hot-plate latency and this lack of effect was unchanged by methysergide. These data support the idea that the antinociceptive effect of low doses of baclofen in the tail-flick test is mediated by disinhibition of a bulbospinal serotonergic projection and release of serotonin in the spinal cord. These data also suggest that the hyperalgesia produced by high doses of baclofen does not result from disinhibition of a serotonergic pain facilitatory pathway, but rather from direct inhibition of tonically-active pain inhibitory neurons in the NRM and NGCp α.

Analysis of excitatory amino acid transmission within the rostral ventromedial medulla: implications for circuitry

Two classes of neurons with distinct responses to opioids have been identified in the rostral ventromedial medulla (RVM), a region with a well-documented role in nociceptive modulation. `On-cells' are directly inhibited by opioids, and opioids can thus gain access to the modulatory circuitry of the RVM by an action on these neurons. `Off-cells' are likely to exert a net inhibitory effect on nociceptive processing, and are activated by opioids. Because the opioid activation of off-cells is indirect, it has been proposed that on-cells function as inhibitory interneurons, and that opioid-induced suppression of on-cell firing in turn activates off-cells via disinhibition. The aim of the present study was to test this possibility. We had previously shown that excitatory amino acid (EAA) neurotransmission is crucial to the nocifensor reflex-related on-cell burst. We therefore infused the non-selective EAA receptor antagonist kynurenate (0.5–2 nmol, 200–500 nl) into the RVM while recording activity of on-, off- and neutral cells in lightly anesthetized rats. Kynurenate infusions produced a significant decrease in on-cell firing, with suppression of the on-cell burst. Off-cells nonetheless continued to display a tail flick-related pause in firing. Tail flick latency was used as an index of nociceptive responsiveness, and was unaffected by kynurenate infusions. These results demonstrate that a burst of on-cell firing is not required in order for the off-cell to exhibit a reflex-related pause in discharge, and do not support the proposed crucial role for on-cells as inhibitory interneurons within the RVM. In addition, preferential suppression of on-cell firing was not associated with an increase in tail flick latency. This suggests that, under the conditions of these experiments, on-cell discharge is not a potent regulator of moment-to-moment variations in nociceptive responsiveness.

Neurobiological and Behavioral Aspects of Recognition in Female Mice

D’AMATO, F. R. Neurobiological and behavioral aspects of recognition in female mice. PHYSIOL BEHAV 62(6) 1311–1317, 1997.—Female mice were tested for their capability to recognize female littermates in adulthood. Sibling females did not show any of the behavioral indices of recognition reported in the literature for sibling males during a 2-h social interaction. Conversely, adult females that experienced 7 days of separation from unrelated cagemates were able to recognize each other: during reunion, they showed reduced olfactory exploration, higher levels of affiliative behavior, and changes in nociception that were opioid dependent. Familiar females treated with naloxone (5.0 mg/kg, i.p.) did not show the increase in tail-flick latency that characterized saline-treated familiar pairs. Unfamiliar females did not show any behavioral modifications during social interaction. These data stress the role of familiarity in female–female social interaction and suggest that more recent experiences conceal earlier information gained before weaning. The importance of familiarity in females was found to be in contrast with the relevance of genetic recognition in male mice, but was well adapted to male and female roles within the social structure of mouse populations.

Role of spinal δ1 and δ2 opioid receptors in the antinociception produced by microinjection of l-glutamate in the ventromedial medulla of the rat

This study examined the contribution of spinal δ 1 and δ 2 opioid receptors to the antinociception produced by microinjection of l-glutamate in either the nucleus raphe magnus (NRM) or the nucleus reticularis gigantocellularis pars α (NGCp α) of the rat. Intrathecal (i.t.) pretreatment with 1 μg of 7-benzylidinenaltrexone (BNTX), a δ 1 opioid receptor antagonist, did not antagonize the increase in tail flick latency (TFL) produced by microinjection of l-glutamate in either the NRM or the NGCp α. In contrast, i.t. pretreatment with 3 μg of naltriben (NTB), a δ 2 opioid receptor antagonist, completely antagonized the increase in TFL evoked by microinjection of l-glutamate in the NRM, but did not antagonize the increase in TFL evoked from the NGCp α. These results suggest that the antinociception produced by activation of these bulbospinal pathways is predominantly mediated by spinal δ 2 opioid receptors and that there is little, if any, contribution by spinal δ 1 opioid receptors.

Dexmedetomidine Injection into the Locus Ceruleus Produces Antinociception

Alpha(2)-Adrenergic agonists such as clonidine and dexmedetomidine are known to produce sedation and analgesia in humans. The sedative effect of these agents is thought to occur through supraspinal pathways, involving the locus ceruleus (LC) and its projections in rats. While the antinociceptive response to alpha(2) agonists, given intrathecally, is mediated predominantly in the spinal cord, other sites of action have not been systematically studied. The authors examined whether alpha(2)-adrenergic receptors in the LC mediate an antinociceptive effect. For administration of different drugs into the LC, guide cannulas were placed with their tips in the LC in male Sprague-Dawley rats. Dexmedetomidine (3.5 micrograms/0.2 microliter) was microinjected into the LC through the cannula, or given systemically by intraperitoneal injecton (50 micrograms/kg). The antinociceptive effect of dexmedetomidine was measured using the tail-flick latency response. To determine the sites through which dexmedetomidine injection into the LC produces antinociception, the authors examined whether this response could be perturbed by the specific alpha(2)-adrenergic antagonists atipamezole and L659,066 and pertussis toxin administered either into the LC or intrathecally before injection of dexmedetomidine systemically or directly into the LC. To eliminate the possibility that drug administered in one site (LC or intrathecal) could reach the other site, the dispositional characteristics of radiolabeled dexmedetomidine (LC) or atipamezole (intrathecal) were studied. Dexmedetomidine placed into the LC produces a dose-dependent increase in the tail-flick latency. This antinociceptive effect was blocked by pertussis toxin and by the alpha(2) antagonists atipamezole and L659,066 placed in the LC. Intrathecal administration of atipamezole and pertussis toxin also blocked the antinociceptive effect of dexmedetomidine placed in the LC. (3)H-dexmedetomidine introduced into the LC did not reach the spinal cord in pharmacologically active concentrations; also, intrathecally administered (3)H-atipamezole did not reach the LC in appreciable amounts. The systemic administration of dexmedetomidine produced an increase in tail-flick latency, and this effect was attenuated by the injection of atipamezole and L659,066 into the LC. Part of the mechanism by which dexmedetomidine produces an antinociceptive effect is by an action directly on the LC, demonstrated by these studies in which antinociception produced by injection of this drug into the LC can be blocked by specific alpha(2) antagonists injected into the LC. Furthermore, the action of dexmedetomidine in the LC in turn may result in an increase in activation of alpha(2) adrenoceptors in the spinal cord, because the antinociceptive effect of LC dexmedetomidine injection also can be blocked by intrathecal injection of antipamezole and pertussis toxin.

Antinociceptive actions of intrathecal xylazine: interactions with spinal cord opioid pathways

We have studied rats with chronically implanted subarachnoid catheters. Xylazine, an alpha 2 adrenoceptor agonist, was injected intrathecally and nociceptive thresholds measured at two skin sites: the tail and the neck. Intrathecal xylazine (dose range 24.3-389 nmol) produced increases in electrical thresholds for nociception in the tail without any change in the neck; this observation suggested that the antinociceptive action of this drug was confined to the caudal part of the spinal cord responsible for tail innervation. The magnitude of this effect was dose-dependent. Tail flick latency also increased in these rats and the antinociceptive effects were antagonized in a dose-dependent manner by the selective alpha 2 adrenoceptor antagonist idazoxan (dose range 6.7-540 nmol). Intrathecal idazoxan also suppressed the increase in tail flick latency caused by the mu opioid agonist fentanyl (0.74 nmol) given intrathecally. This effect was also dose-dependent. The idazoxan dose-response curve for this suppression of fentanyl antinociception assessed with tail flick latency was the same as that for suppression of xylazine. In contrast, the antinociceptive effects of intrathecal xylazine were not affected by concurrent administration of opioid or GABAA antagonists. We conclude that intrathecal xylazine produced spinally mediated antinociceptive effects by combination with spinal cord alpha 2 adrenoceptors and that neither opioid nor GABA-containing propriospinal neurones were involved in the mediation of this effect. However, alpha 2 adrenoceptors in the spinal cord appear to be involved with antinociception produced by intrathecal fentanyl.

Analgesic effects of fibroblast growth factor in the rat

Intraperitoneal (i.p.) injection of acidic fibroblast growth factor (aFGF) to Sprague-Dawley rats induced short-lasting analgesia as measured by tail-flick latency (TFL) test. The maximum effect, a 26% increase in tail-flick latency, was obtained 15 min following 1 μg i.p. aFGF. By 30 min the effect was considerably reduced, and was no longer present by 45 min after treatment. Administration of heat-inactivated aFGF or a hybrid form of aFGF (CLYT/aFGF) that, although active, is unable to cross the blood-brain barrier (BBB), caused no analgesia. Furthermore, the analgesic effects of aFGF were prevented by pretreatment with the nitric oxide synthase inhibitor, l- N G-nitroarginine methyl ester ( l-NAME). Our findings demonstrate an analgesic effect of FGF, which requires crossing of BBB and implicates the nitric oxide pathway.

Ondansetron Blocks Nifedipine-Induced Analgesia in Rats

The serotonergic system is involved in pain transmission and the 5-hydroxytryptamine (5-HT3) receptor subtype mediates some of these effects at the spinal level. Therefore, we explored the effects of the serotonergic system on nifedipine-induced analgesia by using the 5-HT3 receptor antagonist ondansetron. Male Sprague-Dawley rats were pretreated with ondansetron (1 mg/ kg intraperitoneally) or normal saline. After 15 min, rats received injections of nifedipine (15 mg/kg intraperitoneally) or dimethylsulfoxide (DMSO), solvent for nifedipine, as a control. Nociception was assessed by tail-flick method. Rats treated with nifedipine alone had an increase in tail-flick latency of 122%, as measured by the area under the curve, compared to rats treated with DMSO alone. Pretreatment with ondansetron, however completely blocked the analgesic effect of nifedipine, with tail-flick latency remaining at baseline throughout the measurement period. These results indicate that the 5-HT3 receptor plays an important role in the analgesic response to nifedipine and that medications that block this receptor may decrease the analgesic effectiveness of this type of therapy.

Changes in pain threshold during the reproductive cycle of the female rat

Responsiveness to pain was determined in female rats across the whole reproductive cycle using the tail-flick test. When tested immediately after mating, pain thresholds were unaltered, whereas 10 min later animals typically demonstrated hyperalgesia (Experiment 1). They also demonstrated hyperalgesia during most of pregnancy, and had significantly lower pain thresholds than the unmated controls except for the 24 h before parturition, when a sudden increase in tail-flick latencies was recorded (Experiment 2). Pain thresholds were also significantly lower throughout the nursing period but increased significantly when dams were seperated from their litters for 6 h, and returned to premating baseline values within 24 h of weaning (Experiment 3). These findings confirm and extend earlier reports that female reproductive state may significantly modify responsiveness to noxious stimuli, and it is suggested that differences between the results of this and previous studies may be at least partly explained by the relatively stress-free test procedure adopted here.

Analgesic effects of the neurosteroid 3α-androstanediol

The efficacy of 5α-androstane-3α,17β-diol (3α-Androstanediol; 3α-Diol) and 4-pregnen-3,20-dione (progesterone; P) in promoting analgesia was investigated. Ovariectomized rats received daily injections of 3α-Diol (0.6, 3.0, 6.0 and 7.5 mg/kg) or vehicle and twice daily injections of estradiol-17β (E 2: 1 μg) for 2 days. Progesterone (0.5, 1.0, 2.0 and 4.0 mg/kg) or its vehicle was given on the third day and nociceptive testing using the radiant heat tailflick method was carried out 4 h later. In Expt. 1, P and 3α-Diol both produced analgesia and had biphasic dose-response effects when administered singly. 3α-Diol (3.0 mg/kg) elevated tailflick latencies in E 2 -primed animals above those following vehicle, 6.0 or 7.5 mg/kg 3α-Diol; 6.0 and 7.5 mg/kg produced elevations that were greater than vehicle but less than 3.0 mg/kg. Progesterone (0.5 and 1.0 mg/kg) also elevated tailflick latencies above vehicle controls, while 2.0 and 4.0 mg/kg produced intermediate effects. In Expt. 2, 3α-Diol (3α-Diol:BSA) and P (P:BSA) conjugated to bovine serum albumin (BSA) were applied to the medial basal hypothalamus (MBH) and preoptic area (POA) to ascertain whether the steroids' analgesic actions were mediated by membrane actions in these sites. Free P and P:BSA both increased tailflick latencies when applied to the MBH, while 3 α-Diol and 3α-Diol:BSA elevated latencies when applied to the POA, suggesting the steroids' effects occur in part at the neuronal membrane. In Expt. 3, free P or P:BSA applied to the MBH did not increase tailflick latencies if systemic P was given concurrently. Similarly, free 3α-Diol and 3α-Diol:BSA implants into the POA failed to increase tailflick latencies if s.c. 3α-Diol was co-administered. These data indicate that P and 3α-Diol at moderate doses have analgesic effects in part via membrane actions within the MBH and POA, respectively.

Rat strain differences in the potentiation of morphine-induced analgesia by stress

Restraint stress has been shown to increase the magnitude and duration of morphine-induced analgesia; however, this phenomenon has only been investigated using the Sprague-Dawley rat strain. The purpose of this study was to determine if other rat strains would also exhibit a potentiated analgesic response to morphine compared to their unrestrained controls. Dose-response and time course curves for the analgesic effect of morphine (1.0, 3.0, 5.6, 10 mg/kg) were generated in adult, male Wistar, Lewis, Fischer 344, Long-Evans Hooded, and Sprague-Dawley rats either unrestrained or restrained in Plexiglas cylinders, using the tail flick assay. Morphine produced dose-dependent increases in tail flick latencies, and this effect was potentiated by restraint stress in the Sprague-Dawley, Wistar, Lewis, and Fischer 344 strains, but not in the Long-Evans Hooded rats. Because Sprague-Dawley and Wistar rats displayed the most robust stress effect, the use of either of these rat strains is appropriate in studying the mechanisms of stress-induced potentiation of analgesia. The differences among rat strains demonstrated in this study may serve as a basis for correlation with opioid function.

Antinociceptive effect of d-Aspartic acid in mice

The effects of d-and l-aspartic acids on the nociceptive tail flick reflex in mice were investigated. d-Aspartic acid (115–230 mg/kg, IP) was found to increase tail flick latency significantly. Naloxone (0.1 mg/kg) abolished the analgesic effect of d-aspartic acid (115 mg/kg). Morphine and d-aspartic acid, when combined at their nonanalgesic doses, led to significant analgesia. It may be concluded that the opioid system is involved in the antinociceptive effect of d-aspartic acid. Both morphine and d-aspartic acid were previously reported to inhibit l-aspartic acid production via blockade of l-asparaginase. l-Aspartic acid, which was ineffective alone, significantly inhibited the antinociceptive effects of both d-aspartic acid and morphine.

Attenuation of morphine-induced antinociception by L-glutamic acid at the spinal site in rats

The present experimental study was planned to evaluate the effect of intrathecal administration of L-glutamic acid upon antinociception produced by intrathecal morphine in a prospective-controlled manner in conscious freely mobile Sprague-Dawley albino rats. After chronic catheterization of the spinal subarachnoid space, rats were randomly allocated into 12 treatment groups of ten each and the same number of rats served as saline control for the comparison. L-glutamic acid (100 mmol), morphine (1.2 mmol), ketamine (50 mmol) and saline (150 mmol) were injected intrathecally in 5 microliters volumes. Naloxone was injected in a dose of 1 mg.kg-1 im. Immediately before and 15, 30 min, 1, 2 and 3 hr after injection, rats were subjected to a thermal noxious stimulus, using a tail-flick technoanalgesiometer and tail-flick latencies (TFL) were recorded. Intrathecal administration of L-glutamic acid attenuated the antinociceptive effect of intrathecal morphine with a decrease in TFL (1.4 +/- 0.3 sec; P < 0.0001) from 6.6 +/- 0.3 sec. Ketamine led to abolition of this effect (P < 0.01). In rats, pretreated with naloxone, there was restoration as well as augmentation of morphine-induced antinociception in the presence of L-glutamic acid with an increase in TFL (9.0 +/- 0.4 sec; P < 0.0001). We conclude that there is modulation of opioid receptors by L-glutamic acid at the spinal site in rats.

Mechanisms underlying antinociception provoked by heterosegmental noxious stimulation in the rat tail-flick test.

Physiological studies were conducted to examine the effects of noxious stimulation of one hindpaw or one forepaw on the latency of the withdrawal reflex in the tail-flick test in lightly anesthetized spinally intact or transected rats. Male Sprague-Dawley rats were anesthetized with an intraperitoneal injection of a mixture of Na-pentobarbital (20 mg/kg) and chloral hydrate (120 mg/kg). After baseline readings were taken in the tail-flick test, the effects of various noxious stimuli applied to remote body regions were assessed. The noxious stimuli included unilateral or bilateral hindpaw or unilateral forepaw thermal (immersion in water at 55 degrees C for 90 s), unilateral or bilateral chemical (subcutaneous hindpaw injection of 50 microliters of 5% formalin) and unilateral or bilateral mechanical (pinch with clamp exerting a force of 14.75 or 27 N) stimulation. Bilateral chemical and thermal, and unilateral thermal stimulation induced an antinociceptive response, consisting of an increase in tail-flick latency, peaking at 30 s after stimulation. Recovery to baseline levels occurred over the next 3-6 min. The antinociceptive effect of noxious thermal stimulation was attenuated or absent in chronically spinalized animals (T6/7) following hindpaw or forepaw immersion, respectively. Noxious mechanical stimulation had no effect on tail-flick latency. The data provide evidence that a noxious thermal or chemical stimulus produces a heterosegmental antinociceptive effect which is mediated in part via a supraspinal mechanism and in part via a local spinal mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Repetitive exposure to the hot-plate test produces stress induced analgesia and alters β-endorphin neuronal transmission within the periaqueductal gray of the rat

Repetitive exposure of rats to a hot plate induced a novel non-opioid form of stress induced analgesia. The exposure caused a persistent 1.5–2 s increase in tail flick latency which was not attenuated by systemic naltrexone, but was completely inhibited by systemic MK-801. Concomitantly, alterations occurred in the ability to pharmacologically distinguish multiple β-endorphin receptors in the periaqueductal gray. Thus, in response to different forms of stress, different pathways may be activated by β-endorphin, resulting in stress induced analgesias with varied pharmacological characteristics (e.g., opioid and non-opioid).