Selective mu- and kappa-opioid receptor antagonists administered into the nucleus accumbens interfere with rapid tolerance to ethanol in rats

Background  Previous findings have shown that intra-accumbens injection of naltrexone, a non-selective opioid antagonist, blocks the acquisition of rapid tolerance to ethanol in rats. This study investigates the effects of intra-accumbens injection of the selective mu-, delta-, and kappa-opioid antagonists, respectively, naloxonazine, naltrindole, and nor-binaltorphimine, on rapid tolerance to ethanol. Methods  Male Wistar rats with guide cannulae directed to the shell or the core portions of the nucleus accumbens received a microinjection of naloxonazine (2–4 μg), naltrindole (2–4 μg), nor-binaltorphimine (2.5–5 μg), or vehicle. After 5 min, each group was divided in two groups that received ethanol (2.7 g/kg i.p.) or saline. Rats were then tested for motor coordination on the tilting plane apparatus. Twenty four hours later, all rats received a challenge dose of ethanol (2.7 g/kg i.p.) and were tested on the tilt plane again. Results  Repeated injections of ethanol caused a reduction in motor impairment suggesting the development of tolerance. However, rats injected with 4 μg naloxonazine into either core or shell portions of the nucleus accumbens did not exhibit tolerance when challenged with ethanol on day 2. Rats treated with 5 μg nor-binaltorphimine into accumbens core plus intraperitoneal saline on day 1 showed reduced motor impairment when challenged with ethanol on day 2, suggesting cross-tolerance to ethanol. Conclusions  Taken together, our results suggests that mu-opioid receptors in both shell and core portions of the nucleus accumbens, and possibly kappa-opioid in the core, participate in the modulation of rapid tolerance to ethanol.     

耳针对结直肠扩张导致大鼠内脏痛的影响

目的 研究耳针对结直肠扩张(CRD)所造成大鼠内脏痛的影响.方法 29只SD大鼠随机分为空白对照组(A组,7只)、模型组(B组,7只)、耳针组(C组,8只)和假针刺组(D组,7只).连续记录大鼠CRD前后、干预期及干预后各30 min的肌电图(EMG)和心率变异性(HRV),采用荧光定量PCR观察结肠中5-羟色胺1A(5-HTIA)受体mRNA的表达.结果 CRD后,B、C、D组EMG均较A组显著升高(P＜0.05),但HRV与扩张前比较无统计学差异(P＞0.05).C组EMG和5-HT1A受体mRNA表达较B组、D组明显降低(P＜0.05).结论 耳针可有效改善CRD导致的大鼠内脏痛.这种调节作用可能与5-HT递质受体系统有关.     

A comparative study in rats of the respiratory depression and analgesia induced by mu- and delta-opioid agonists

A comparison was made in awake rats between the analgesic and the respiratory depressant actions induced by the mu-opiate agonists morphine and Tyr-D-Ala-Gly-N-Me-Phe-Met-(O)-ol (FK-33824), and the delta-agonists Tyr-D-Ala-Gly-Phe-D-Leu ( DADLE ) and Tyr-D-Ser-Gly-Phe-D-Leu-Thr (D-Ser2- Thr6 ), injected into the cerebral ventricles. The four opioids caused a dose-dependent analgesia (tail-flick); FK-33824 was the most potent, followed by morphine, DADLE and D-Ser2- Thr6 , and the duration of the analgesic effect of D-Ser2- Thr6 was very short. Respiratory frequency was dose-dependently depressed by FK-33824 and DADLE ; dose-response curves with morphine and D-Ser2- Thr6 could not be obtained for technical reasons. The in vivo apparent pA2 values for naloxone against the mu-agonist FK-33824 and the delta-agonist DADLE were similar in analgesia suggesting an interaction with the same type of receptor. On the other hand, in respiration studies the pA2 value for the interaction of naloxone with DADLE was significantly higher than with FK-33824. The ratio between the ED50 required to induce respiratory depression and analgesia was 1,500 times higher for FK-33824 than for DADLE . It was concluded that agonist interaction with mu-receptors can result in antinociceptive effect in the tail-flick test, whereas respiratory depression seems to require a prominent, but non-exclusive, interaction with delta-receptors.     

Oral clonidine inhibits visceral pain-related viscerosomatic and cardiovascular responses to colorectal distension in rats

The alpha(2)-adrenoceptor agonist, clonidine, modulates colorectal sensorimotor functions in humans and, given intrathecally, has analgesic effects in the colorectal distension (CRD) model in rats. We tested the effects of systemic clonidine on the visceral pain-related viscerosomatic and autonomic cardiovascular responses to CRD and colonic compliance in rats using clinically relevant CRD protocols. The activity of the abdominal musculature (viscerosomatic response), monitored by electromyography and intracolonic manometry, and changes in arterial blood pressure and heart rate, monitored by telemetry, were assessed simultaneously in conscious rats during CRD. Pressure-volume relationships during CRD served as a measure of colonic compliance. Clonidine (50-200 nmol/kg, p.o.) dose-dependently inhibited the viscerosomatic response to phasic, noxious CRD (12 distension at 80 mm Hg). At 200 nmol/kg clonidine also attenuated the increase in blood pressure (70+/-7% inhibition, P<0.05) and heart rate (67+/-16% inhibition, P<0.05) associated to noxious CRD. Similar effects were observed after i.v. administration. Likewise, clonidine (200 nmol/kg, p.o.) reduced the response to ascending phasic CRD (10-80 mm Hg) and significantly increased the threshold pressure for pain-related responses. Clonidine (50 or 150 nmol/kg, i.p.) did not affect the pressure-volume relationship during phasic CRD (2-20 mm Hg). These results show that systemic clonidine, at doses devoid of visible side effects, has analgesic effects in the CRD model of visceral pain in rats without affecting colonic compliance. These observations confirm the analgesic activity of systemic clonidine on visceral pain, support the translational value of the rat CRD model to humans and show that manometry is more sensitive than electromyography detecting pain-related responses.     

Serotonin-GABA interactions in the modulation of mu- and kappa-opioid analgesia

In the present study, we studied the interaction between serotonergic (5-HTergic) and gamma-aminobutyric acid (GABA)-ergic systems in the modulation of analgesia from morphine, a mu-opioid agonist, and U50,488, a kappa-opioid agonist. All experiments were performed in mice using the 49 degrees C tail-withdrawal assay. The benzodiazepine receptor agonist, diazepam, the serotonin synthesis inhibitor, para-chlorophenylalanine (p-CPA), and the 5-HT(1A) receptor agonist, 8-OH-DPAT, were all found to attenuate morphine and U50,488 analgesia. In each case, the attenuation was itself blocked by treatment with L-5-HTP, a serotonin precursor, bicuculline, a GABA(A) receptor antagonist or picrotoxin, a GABA(A)-gated chloride channel blocker. Neither L-5-HTP nor the GABA(A) receptor antagonists were found to affect morphine or U50,488 analgesia per se. Thus, these findings indicate that a benzodiazepine-GABAergic agent (diazepam) attenuates opioid analgesia through the serotonergic system, and antiserotonergic agents (8-OH-DPAT, p-CPA) attenuate opioid analgesia through the GABAergic system. The intimate interactions between GABA and serotonin in the present study further suggest that these neurotransmitters work in complex ways together rather than alone in the modulation of opioid analgesia.     

Antinociceptive effects of the selective delta opioid agonist SNC80 alone and in combination with mu opioids in the squirrel monkey titration procedure

Abstract Rationale. The nonpeptidic compound SNC80 [(+)-4[(αR)-α-((2S, 5R)-4-allyl-2, 5,-dimethyl-l-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide], has a high degree of selectivity for delta opioid receptors. Moreover, compounds with delta opioid activity have been shown to enhance the effects of mu agonists under certain conditions. Objectives. The present study examined the effects of SNC80 alone and in combination with the mu opioid agonists, morphine, butorphanol, and buprenorphine to determine whether SNC80 would enhance their antinociceptive effects. Methods. In the squirrel monkey shock titration procedure increasing levels of shock are delivered to the monkey's tail in incremental steps and responses on a lever decrease shock intensity. The level at which monkeys maintain the shock (median shock level, MSL) and rate of responding (RR) are examined. Results. SNC80 alone did not consistently alter responding under the titration procedure; however, morphine, butorphanol, and buprenorphine increased MSL without decreasing RR markedly. SNC80 (0.1–3.0 mg/kg) enhanced the effects of single doses of morphine, butorphanol, and buprenorphine that either did not increase or produced very small increases in MSL when administered alone. Interestingly, SNC80 enhanced the effects of morphine, butorphanol, and buprenorphine on MSL without decreasing RR. Conclusions. SNC80 does not produce antinociceptive effects in the squirrel monkey titration procedure but can enhance the effects of selected doses of morphine, butorphanol, and buprenorphine on MSL without decreasing RR. These data suggest that SNC80-induced enhancement of the antinociceptive effects of mu opioids is dependent on dose, time, and method of administration and is not the result of sedation or motor dysfunction. Electronic Publication     

Sex-related differences in mechanical nociception and antinociception produced by mu- and kappa-opioid receptor agonists in rats

Previous studies indicate that in antinociceptive procedures employing thermal, chemical and electrical stimuli, opioids are generally more potent in male than female rodents. The purpose of the present study was to examine nociception and opioid antinociception in male and female rats using a mechanical nociceptive stimulus. Results indicated that males had a higher threshold for nociception, and in tests in which a constant pressure was applied to the hindpaw, the paw withdrawal latencies were consistently longer in males. Opioids with activity at the mu receptor, including levorphanol, morphine, dezocine, buprenorphine, butorphanol and nalbuphine, were generally more potent and/or effective in males. In contrast, sex differences were not consistently observed with the kappa-opioid receptor agonists spiradoline, (5,7,8b)-N-methyl-N[2-1(1-pyrrolidinyl),1-oxaspiro[4,5]dec-8-yl benzeneacetamide (U69593), trans-(+/-)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50488), enadoline, ethylketocyclazocine, and nalorphine. These findings suggest that males and females differ in their responsiveness to mechanical nociception and that sex differences in sensitivity to kappa-, but not mu-, opioid receptor agonists are specific to certain nociceptive stimulus modalities.     

Effects of mu- and kappa-opioid receptor agonists on urinary output in mice

The effects of ethylketazocine, morphine, bremazocine and naloxone were determined on urinary output and weight loss in Cox mice. Morphine and fentanyl were also studied in Harlan mice. Bremazocine, ethylketazocine and morphine markedly increased urinary output and weight loss within 5 hr after injection. Naloxone antagonized the diuretic actions of morphine (5 mg/kg) and bremazocine (0.06 mg/kg) over a similar dose range (0.3--10 mg/kg). By comparison with the other agonists, fentanyl had little effect on urinary output or weight loss. These results suggest that kappa agonist activity increases urinary output in mice just as reported for rats. The data also suggest that in mice morphine has some kappa agonist activity, whereas fentanyl does not.     

Involvement of mu-, delta- and kappa-opioid receptor subtypes in the discriminative-stimulus effects of delta-9-tetrahydrocannabinol (THC) in rats

Rationale Many behavioral effects of delta-9-tetrahydrocannabinol (THC), including its discriminative-stimulus effects, are modulated by endogenous opioid systems.Objective To investigate opioid receptor subtypes involved in the discriminative effects of THC.Methods Rats trained to discriminate 3 mg/kg i.p. of THC from vehicle using a two-lever operant drug-discrimination procedure, were tested with compounds that bind preferentially or selectively to either mu-, delta- or kappa-opioid receptors.Results The preferential mu-opioid receptor agonist heroin (0.3–1.0 mg/kg, i.p.), the selective delta-opioid receptor agonist SNC-80 (1–10 mg/kg, i.p.) and the selective kappa-opioid receptor agonist U50488 (1–10 mg/kg, i.p.) did not produce generalization to the discriminative effects of THC when given alone. However, heroin, but not SNC-80 or U50488, significantly shifted the dose–response curve for THC discrimination to the left. Also, the preferential mu-opioid receptor antagonist naltrexone (0.1–1 mg/kg, i.p.), the selective delta-opioid receptor antagonist, naltrindole (1–10 mg/kg, i.p.) and the kappa-opioid receptor antagonist nor-binaltorphimine (n-BNI, 5 mg/kg, s.c.), did not significantly reduce the discriminative effects of the training dose of THC. However, naltrexone, but not naltrindole or n-BNI, significantly shifted the dose–response curve for THC discrimination to the right. Finally, naltrexone, but not naltrindole or n-BNI, blocked the leftward shift in the dose–response curve for THC discrimination produced by heroin.Conclusions mu- but not delta- or kappa-opioid receptors are involved in the discriminative effects of THC. Given the role that mu-opioid receptors play in THCs rewarding effects, the present findings suggest that discriminative-stimulus effects and rewarding effects of THC involve similar neural mechanisms.     

Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats

Our previous work indicated that pretreatment with the selective kappa-opioid receptor (KOPr) agonist, U69593, attenuated the ability of priming injections of cocaine to reinstate extinguished cocaine-seeking behavior. The present study expanded these initial tests to include other traditional KOPr agonists, U50488H, spiradoline (SPR), and salvinorin A (Sal A), an active constituent of the plant Salvia divinorum. Following acquisition and stabilization of cocaine self-administration, cocaine-produced drug-seeking was measured. This test was conducted in a single day and comprised an initial phase of self-administration, followed by a phase of extinguished responding. The final phase examined reinstatement of extinguished cocaine self-administration followed by a priming injection of cocaine (20.0 mg/kg, intraperitoneal (I.P.)) in combination with the various KOPr agonists. Cocaine-induced drug-seeking was attenuated by pretreatment with U69593 (0.3 mg/kg, subcutaneous (S.C.)), U50488H (30.0 mg/kg, I.P.), SPR (1.0, 3.0 mg/kg, I.P.) and Sal A (0.3, 1.0 mg/kg, I.P.). Sal A (0.3, 1.0 mg/kg, I.P.) had no effect on operant responding to obtain sucrose reinforcement or on cocaine-induced hyperactivity. These findings show that Sal A, like other traditional KOPr agonists attenuates cocaine-induced drug-seeking behavior.     

Effect of insulin hypoglycemic stress on nociceptive responses to mu- and kappa-opioid receptor agonists at LH-surge in female rats

In a randomized, prospective, controlled and crossover study, the effects of insulin hypoglycemic stress on nociceptive responses to mu- and kappa-opioid receptor directed drugs during steroid-induced preovulatory LH-surge were seen in ovariectomized female rats. Ovariectomized rats were equally distributed in two groups of 10. In group 1 rats, LH-surge was induced by sequential treatment with estradiol benzoate 7.5 micro g/rat s.c. and progesterone 5 mg/rat s.c., whereas in group 2 rats, vehicles of estradiol benzoate and progesterone were given in a sequential manner. A third group consisted of sham-operated rats, which received no treatment. Rats were exposed to insulin-induced hypoglycemic stress 1 h before the peak of LH-surge. Antinociceptive responses of morphine, buprenorphine and pentazocine were observed at peak LH-surge during hypoglycemic stress. Increased nociceptive responses to noxious stimulus and decreased percent maximal possible effect for morphine, buprenorphine and pentazocine at LH-surge were significantly (p < 0.01) reversed during insulin hypoglycemic stress. There was a significant (p < 0.01) decrease in the ED(50) values of morphine, buprenorphine and pentazocine during hypoglycemic stress. The present study indicates that insulin hypoglycemic stress is responsible for increased antinociceptive activities of morphine, buprenorphine and pentazocine and decreased sensitivity to noxious stimulus in ovariectomized rats with or without steroid-induced LH-surge.     

鞘内注射纳洛酮对小剂量丙泊酚抗内脏伤害作用的影响

目的研究丙泊酚内脏痛镇痛机制是否与脊髓阿片受体有关。方法56只成年雄性SD大鼠蛛网膜下腔埋入导管后随机均分为8组，分别鞘内预注生理盐水（NS）或纳洛酮2μg／只、4μg／只或8μg／只，再腹腔注射NS或丙泊酚10mg／kg，随后采用结直肠扩张的内脏痛实验动物模型，以腹壁明显收缩变平的最小扩张压力值作为内脏痛反应（VMR）阈值，观察大鼠60min内内脏痛阈的变化。结果单纯腹腔注射小剂量丙泊酚后，5～25min内大鼠内脏痛阈显著升高（P〈0．01），10min达高峰（％MPE=37．2％）；单纯鞘内预注不同剂量纳洛酮大鼠内脏痛阈无明显变化（P〉0．05）；先鞘内预注不同剂量纳洛酮再腹腔注射丙泊酚后，丙泊酚所致抗内脏伤害作用被不同程度的减弱。结论（1）小剂量丙泊酚对内脏伤害刺激具有抑制作用；（2）纳洛酮剂量依赖、时间依赖地拮抗丙泊酚的抗内脏伤害作用，其作用机制与脊髓阿片受体有关。     

Regional haemodynamic effects of mu-, delta-, and kappa-opioid agonists microinjected into the hypothalamic paraventricular nuclei of conscious, unrestrained rats.

1. The cardiovascular effects of bilateral injection into the hypothalamic paraventricular nuclei of selective mu-, delta-, and kappa-opioid receptor agonists were investigated in conscious, unrestrained Wistar Kyoto rats, chronically instrumented with pulsed Doppler flow probes for measurement of regional haemodynamics. 2. The selective mu-agonist [D-Ala2,MePhe4,Gly5ol]enkephalin (DAMGO), injected bilaterally into the hypothalamic paraventricular nuclei (0.01-1.0 nmol), caused increases in blood pressure, tachycardias, vasoconstriction in renal and superior mesenteric vascular beds and substantial vasodilatation in the hindquarter vascular bed. 3. The administration of increasing doses (0.01-5.0 nmol) of the selective delta-agonist [D-Phe2,5]enkephalin (DPDPE) or the selective kappa-agonist, U50488H into the paraventricular nuclei (PVN) had no significant effect on blood pressure, heart rate, or regional haemodynamics. 4. Together, the present results are further evidence of a role for opioid peptides, especially acting at mu-receptors in the PVN, in the central regulation of the cardiovascular system, whereas a role for opioid peptides, acting at delta- and kappa-receptors in the PVN, seems less obvious from the present results.     

Differential cross-tolerance to mu and kappa opioid agonists in morphine-tolerant rats responding under a schedule of food presentation

If different populations of opioid receptors mediate the actions of mu and kappa opioid agonists, then tolerance induced by the chronic administration of a mu agonist should confer cross-tolerance to other mu agonists but not necessarily to those compounds whose effects are mediated by the kappa receptor. This hypothesis was evaluated in the present investigation by examining the effects of the mu agonists morphine,l-methadone and fentanyl, the kappa agonists U50,488 and bremazocine, and the mixed kappa/mu agonist ethylketocyclazocine in rats responding under a fixed-ratio 30 schedule of food presentation before, during and after exposure to a regimen of chronic morphine administration. For comparison, naloxone was evaluated as a representative mu antagonist and the phenothiazine chlorpromazine as a control drug. During all phases of the experiment, each of these compounds produced dose-related decreases in rate of responding. During the daily administration of 40 mg/kg morphine, tolerance developed to the rate-decreasing effects of morphine,l-methadone and fentanyl, and an enhanced sensitivity to the effects of naloxone. In contrast to the effects obtained with these mu opioids, there was no evidence that chronic morphine administration produced tolerance or enhanced sensitivity to the rate-decreasing effects of U50,488, bremazocine, ethylketocyclazocine and chlorpromazine. The present findings demonstrate that the chronic administration of morphine results in the selective development of tolerance to other mu agonists. In addition, the lack of cross-tolerance between morphine and the kappa agonists examined demonstrate that this behavioral preparation is a useful tool for differentiating the effects of compounds acting at different opioid receptor types.     

Stereoselective effects of opiate agonists and antagonists on ingestive behavior in rats

In male Sprague Dawley rats, the (?)-isomer of the opiate antagonist GPA 1843 (β-9-methyl-5-phenyl-2-allyl-2′-hydroxy-6, 7-benzomorphan) produced dose-related decreases in nocturnal feeding and of hyperphagias induced by 2-deoxy-D-glucose (2-DG; 400 mg/kg) and 24 hr food deprivation (FD). The hyperphagia induced by insulin (10 U/kg) was not significantly decreased by GPA 1843. In contrast, comparable doses of the (+)-stereoisomer, GPA 1847, had no effect on nocturnal, 2-DG or FD hyperphagia. In addition, hyperphagia and hyperdipsia were observed following administration of the opiate agonist levorphanol, but not its stereoisomer, dextrorphan. Thus, the effects of these agents on consummatory behavior are mediated by a stereospecific interaction with opiate receptors, which further indicates that endogenous opiate peptides are involved in the expression of these opiate-related hyperphagias.     

Role of mu- and delta-opioid receptors in the nucleus accumbens in turning behaviour of rats

The role of mu-, delta1- and delta2-opioid receptors in the nucleus accumbens in pivoting was investigated in freely moving rats. Unilateral injections of the mu-opioid receptor agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO, 1 and 2 microg) and the delta2-opioid receptor agonist, deltorphin II (1 and 2 microg), but not the delta1-opioid receptor agonist, [D-Pen(2,5)]-enkephalin (DPDPE, 1-4 microg), into the shell or the core of the nucleus accumbens significantly induced contraversive pivoting. The pivoting induced by DAMGO (2 microg) and deltorphin II (2 microg) was inhibited significantly by the mu-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (CTOP, 0.1 and 1 microg), and the delta2-opioid receptor antagonist, naltriben (NTB, 0.1 and 1 mg/kg, i.p.), respectively. The DAMGO (2 microg)- or deltorphin II (2 microg)-induced pivoting was also inhibited significantly by co-administration of the dopamine D1/D2 receptor antagonist, cis(Z)-flupentixol (1 and 10 microg). The pivoting induced by unilateral injections of a mixture of dopamine D1 (SKF 38393, 5 microg) and D2 (quinpirole, 10 microg) receptor agonists into the shell was significantly inhibited by cis(Z)-flupentixol (1 and 10 microg) or NTB (1 and 3 mg/kg, i.p.), but not CTOP (1 microg) or delta1-opioid receptor antagonist, (E)-7-benzylidenenaltrexone (1 mg/kg, i.p.). The contraversive pivoting elicited by the cholinergic agonist, carbachol (5 microg), into the core was inhibited by co-administration of the muscarinic M1 antagonist, pirenzepine (1 microg), but not cis(Z)-flupentixol (1 microg). The results suggest that unilateral activation of mu- or delta2-opioid, but not delta1-opioid, receptors in the core and/or shell of the nucleus accumbens elicits contraversive pivoting that requires intact dopamine D1/D2 receptors in the shell, but not intact muscarinic M1 mechanism in the core. The study also shows that delta2-opioid, but not mu- and delta1-opioid, receptors in the core and/or shell modulate the shell-specific, dopamine D1/D2 receptor mechanisms involved in the production of pivoting.     

The GABA(B) receptor agonist, baclofen, and the positive allosteric modulator, CGP7930, inhibit visceral pain-related responses to colorectal distension in rats

Activation of GABA(B) receptors by the selective agonist baclofen produces anti-nociceptive effects in animal models of somatic pain. The aim of the present study was to evaluate the effect of baclofen and the GABA(B) receptor positive allosteric modulator CGP7930 on pseudo-affective responses to colorectal distension in rats. Female Sprague-Dawley rats were subjected to repeated, noxious colorectal distension (CRD) (12 distensions at 80 mmHg, for 30 s with 5 min intervals). The visceromotor response (VMR) and cardiovascular responses (mean arterial blood pressure (ABP) and heart rate (HR)) to CRD were monitored in conscious, telemetrized animals. Baclofen (0.3-3 micromol/kg, i.v.) reduced the VMR to CRD dose-dependently, reaching a 61% maximal inhibition (p < 0.001). The highest doses of baclofen attenuated CRD-evoked increases in ABP by 17% (p > 0.05) and reduced the change in HR by 48% (p < 0.01). CGP7930 (3-30 micromol/kg, i.v.) reduced the VMR to CRD in a dose-dependent fashion with a maximal inhibition of 31% (p < 0.05). The highest dose of CGP7930 also attenuated the increase in ABP by 18% (p > 0.05) and inhibited the increase in HR by 24% (p < 0.05) associated with CRD. Neither baclofen nor CGP7930 affected colorectal compliance. The results suggest that activation of GABA(B) receptors produces anti-nociceptive effects in a rat model of mechanically induced visceral pain. While CGP7930 was less efficacious than baclofen overall, positive allosteric modulation of GABA(B) receptors may represent a valid approach in the treatment of visceral pain conditions, with the possibility of an improved safety profile compared to full agonism.     

Effect of mu- and kappa-opioid agonists on the electroconvulsive seizure threshold in mice and antagonism by naloxone and MR 2266

The effects of mu-agonists (morphine, fentanyl) and kappa-agonists (U-50,488, U-69,593, bremazocine, nalbuphine, tifluadom) on the electroconvulsive threshold were studied in mice. The threshold could be significantly elevated by all drugs tested in a dose range that was in the order of magnitude of the antinociceptive ED50. Mice tolerant to the antielectroshock effect of morphine still reacted to U-69,593. The antagonism of the anticonvulsant effect by the mu-antagonist naloxone and the kappa-antagonist MR 2266 was receptor-specific only with fentanyl and U-50,488. The other opioid agonists were either antagonized by both drugs (morphine, U-69,593, bremazocine, nalbuphine) or even by the opposite antagonist (tifluadom). A synergistic effect of mu- and kappa-stimulation is assumed for the mediation of the antielectroshock effect of opioid drugs, but drugs with high affinity and intrinsic activity at one receptor type (fentanyl, U-50,488) are obviously able to bring about their antielectroshock effect through the one respective opioid binding site.     

Differential sensitivity of models of antinociception in the rat, mouse and guinea-pig to mu- and kappa-opioid receptor agonists.

1 A range of opioid receptor agonists were tested for activity in five antinociceptive models: the acetylcholine-induced abdominal constriction, tail-flick and hot plate tests in the mouse and the paw pressure test in the rat and guinea-pig. 2 Agonists acting preferentially at the kappa-opioid receptor were significantly more potent in the guinea-pig than in the rat paw pressure test, whereas mu-receptor preferring agonists were equipotent in the two tests. The mouse abdominal constriction test was of equal sensitivity to the guinea-pig pressure test for both types of agonist. 3 The mouse tail-flick and hot plate tests were progressively less sensitive than the other three tests, particularly to kappa-receptor preferring agonists. 4 The efficacy of an agonist can also markedly affect its activity in antinociceptive tests. Thus, partial kappa-agonists were weak or inactive in the rat paw pressure test, and partial agonists at both mu- and kappa-opioid receptors were relatively weak in the tests in which heat was the noxious stimulus, particularly the mouse hot plate test. 5 The mouse abdominal constriction test is suggested as the most appropriate antinociceptive model for testing a broad range of opioid agonists, whilst the relative potency of a drug in the rat and guinea-pig paw pressure tests may indicate the degree to which it is selective for kappa-opioid receptors in vivo.     

Efficacy and safety of fentanyl sublingual spray for the treatment of breakthrough cancer pain: a randomized,double-blind,placebo-controlled study

Abstract

Background and objectives:

A number of transmucosal fentanyl formulations have been developed for the management of breakthrough cancer pain (BTCP). Sublingual delivery of fentanyl, formulated as fentanyl sublingual spray, offers the potential for more rapid and greater absorption of fentanyl and associated onset of analgesic effect compared with other formulations. The objective of this study was to assess the efficacy and safety of fentanyl sublingual spray for the treatment of BTCP.