Effects of systemically administered monoamine reuptake blocking agents on patterns of buspirone-induced analgesia in rats

We have recently shown the serotonin 5-HT1A receptor agonist buspirone to produce analgesia in several pain tests in rats. As a 5-HT1A agonist, buspirone may change serotonergic (5-HT) tone to alter the balance of central monoaminergic (MA) systems that function in analgesia. MA-reuptake blocking drugs have been shown to produce analgesia, both when given alone and in combination with a variety of other agents, presumably via their action upon MA neurochemistry. The present study was undertaken to examine the effect of systemic administration of the 5-HT-reuptake blocker amitriptyline (AMI: 10 mg/kg), NE-reuptake blocker desipramine (DMI: 10 mg/kg) or DA-reuptake blocker GBR-12909 (7.5 mg/kg) on patterns of analgesia produced by buspirone (1-5 mg/kg) in thermal and mechanical pain tests in rats. Neither reuptake blocking agents or buspirone, when administered alone or in combination, produced overt changes in motor activity at the doses tested. AMI alone was not analgesic in either thermal or mechanical pain tests. In both assays, AMI reduced the analgesic action of buspirone, with greater effects seen in the thermal test. When administered alone, DMI produced significant analgesia against thermal and mechanical pain. DMI significantly attenuated the analgesic action of all doses of buspirone in both pain tests. Alone, GBR-12909 did not affect nociception in thermal or mechanical tests. GBR-12909 decreased buspirone-induced analgesia at all doses in the thermal test, while having no effect on buspirone-induced analgesia against mechanical pain. These results demonstrate that facilitation of 5-HT, NE and DA function with reuptake blocking drugs did not enhance the analgesic action of buspirone. These data indicate against the adjuvant use of reuptake blocking compounds and buspirone as analgesics. Furthermore, such findings may suggest other possible non-MA substrates of buspirone-induced analgesia.     

Possible analgesic and anti-inflammatory interactions of aspartame with opioids and NSAIDs

The purpose of the present study was to investigate analgesic and anti-inflammatory properties of aspartame, an artificial sweetner and its combination with various opioids and NSAIDs for a possible synergistic response. The oral administration of aspartame (2-16mg/kg, po) significantly increased the pain threshold against acetic acid-induced writhes in mice. Co-administration of aspartame (2mg/kg, po) with nimesulide (2 mg/kg, po) and naproxen (5 mg/kg, po) significantly reduced acetic acid-induced writhes as compared to effects per se of individual drugs. Similarly when morphine (1 mg/kg, po) or pentazocine (1 mg/kg, po) was co-administered with aspartame it reduced the number of writhes as compared to their effects per se. Aspartame (4,8,16 mg/kg, po) significantly decreased carrageenan-induced increase in paw volume and also reversed the hyperalgesic effects in rats in combination with nimesulide (2 mg/kg, po).The study indicated that aspartame exerted analgesic and anti-inflammatory effects on its own and have a synergistic analgesic response with conventional analgesics of opioid and non-opioid type, respectively.     

Analgesic effects of tramadol, carprofen or multimodal analgesia in rats undergoing ventral laparotomy

In this study, the authors evaluated the analgesic efficacy of tramadol (an opioid-like analgesic), carprofen (a nonsteroidal anti-inflammatory drug) and a combination of both drugs (multimodal therapy) in a rat laparotomy model. The authors randomly assigned rats to undergo either surgery (abdominal laparotomy with visceral manipulation and anesthesia) or anesthesia only. Rats in each group were treated with tramadol (12.5 mg per kg body weight), carprofen (5 mg per kg body weight), a combination of tramadol and carprofen (12.5 mg per kg body weight and 5 mg per kg body weight, respectively) or saline (anesthesia control group only; 5 mg per kg body weight). The authors administered analgesia 10 min before anesthesia, 4 h after surgery or (for the rats that received anesthesia only) anesthesia and 24 h after surgery or anesthesia. They measured locomotor activity, running wheel activity, feed and water consumption, body weight and fecal corticosterone concentration of each animal before and after surgery. Clinical observations were made after surgery or anesthesia to evaluate signs of pain and distress. The authors found that carprofen, tramadol and a combination of carprofen and tramadol were all acceptable analgesia regimens for a rat laparotomy model.     

多模式镇痛在全膝关节置换术中的疗效评价

目的：探讨联合关节周围注射镇痛药物和持续静脉镇痛的多模式镇痛对全膝关节置换术（total knee arthroplasty,TKA）患者功能恢复的疗效。方法：60例拟行单侧TKA的患者完全随机分为实验组（28例）和对照组（28例）。所有患者术前48 h开始服用塞来昔布（西乐葆）200 mg/次,每天2次。实验组患者术中膝关节周围注射镇痛药物,术后给予持续静脉镇痛（continuous intravenousanalgesia,CIA）。对照组患者没有运用关节周围注射药物,仅给予术后CIA。记录术后CIA用量、各时间点静止视觉模拟疼痛评分（rest visual analogue score,RVAS）、被动活动视觉模拟疼痛评分（passive visual analogue score,PVAS）和膝关节活动度（range of mo-tion,ROM）,同时观察药物的毒副作用。结果：（1）实验组术后24、48 h内PCA的用量均显著低于对照组（P〈0.05）。（2）实验组术后4、8、12、24、48 h的RVAS和24、48 h的PVAS均显著低于对照组（P〈0.05）;术后72 h两组间RVAS和PVAS的差异均无统计学差异（P〉0.05）。（3）实验组术后第1、2、3 d的ROM均显著高于对照组（P〈0.05）,术后第l、2 w两组ROM之间的差异无统计学意义（P〉0.05）;实验组术后主动屈膝到90？所需的天数显著低于对照组（P〈0.05）。（4）实验组中恶心、呕吐和追加药物的发生率均显著低于对照组（P〈0.05）,未发现伤口感染、延期愈合及组织坏死等并发症。结论：联合使用关节周围注射镇痛药物和持续静脉镇痛的多模式镇痛方案,可以有效的缓解TKA患者术后早期的疼痛,促进患者膝关节的功能恢复,减少了单一用药所产生的不良反应。该方案安全有效、操作简单,是一种值得推广的TKA术后镇痛方法。     

Electric stimulation of the dental pulp in the evaluation of the central effect of analgesics

We conducted a double-blind cross-over study in ten volunteers aged from 19 to 30 years, to compare the pain control effects of a single oral dose of two analgesic compounds (drug A: propyphenazone mg 250, ethylmorphine mg 5, caffeine mg 5; drug B: dipyrone mg 500, diphenhydramine mg 12.5, adiphenine mg 5, ethyl aminobenzoate mg 2.5) in an experimental pain model using stimulation of dental pulp. Constant voltage stimuli were delivered through silver chloride electrodes placed in contact with the vestibular surface of the upper medial incisor. At the beginning of the session, the pain input was graded by asking the subject to identify the weakest stimulus perceived (threshold level) and the strongest stimulus endurable (tolerance level). The range between threshold and tolerance level was divided in nine steps plus a subliminal step. The ten steps were delivered randomly, and each series of steps was repeated eight times. The subjects were instructed to rate the pain sensation in an arbitrary scale of 5 degrees. The procedure was repeated at 60 min and 180 min after drug administration. Each subject received two tablets of drug A or drug B in two different sessions at weekly intervals. Statistical analysis of the procedures showed that neither drug A nor drug B significantly affected the pain threshold. Drug A significantly reduced the total pain score (P less than 0.01) and its action peaked 60 min after administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

The mGluR5 Antagonist Fenobam Induces Analgesic Conditioned Place Preference in Mice with Spared Nerve Injury

Antagonists of metabotropic glutamate receptors (mGluRs) have the potential to act as analgesic drugs that may help alleviate chronic pain. This study was done to look at the possible rewarding properties of the mGluR5 antagonist, fenobam, in a cognitive assay. Analgesic conditioned place preference (aCPP) was used to examine the effects of fenobam (30 mg/kg) and the prototypical mGluR5 antagonist, MPEP, and these effects were compared to those of a drug with known analgesic properties, morphine (10 mg/kg). In each experiment, one group of mice received spared nerve injury (SNI) surgery to model chronic pain; the other group received a control sham surgery. Both fenobam and MPEP induced preference in the SNI mice, such that SNI mice spent significantly more time in the mGluR5 antagonist-paired chamber compared to a vehicle-paired chamber. No such preference developed for sham mice. Morphine induced preference in male and female mice in both the SNI and sham groups. The results showed that fenobam and MPEP likely reduced on-going distress in the SNI mice, causing them to prefer the chamber paired with the drug compared to the vehicle-paired chamber. Since sham animals did not prefer the drug-paired chamber, these data demonstrate that mGluR5 antagonism is non-rewarding in the absence of pain-like injury.     

Antinociceptive effect of amitriptyline in mice of acute pain models

Tricyclic antidepressant drugs induce antinociceptive effect and suggest that their analgesic action could be related to the monoaminergic activity of the drugs. The analgesic activity of amitriptyline was observed in mouse models of acute pain. Mice were divided into different groups and were given amitriptyline in different doses alone and in combination with morphine. Reaction time in Hot-Plate and Tail-Flick tests was observed. Results showed that amitriptyline had antinociceptive effect in acute pain state in experimental models. Amitriptyline in combination with morphine had better analgesic effect than the morphine alone in Hot-Plate test.     

Augmentation of analgesic effect of ibuprofen by alprazolam in experimental model of pain

The reports of analgesic effects of benzodiazepines are inconsistent. There is evidence of a hyperalgesic effect induced by activation of supraspinal GABAA receptors and an antinociceptive effect induced by activation of receptors located in the spinal cord (dorsal horns). The aim of the study was to discover whether the systemic administration of a benzodiazepine agent alprazolam increases the systemic analgesic efficacy of non-opioid analgesic ibuprofen. Experimental studies combining these agents have not yet been published. We used three experimental methods - writhing test (with acetic acid), tail-flick test and plantar test to assess analgesic action. The drugs were administered orally. Augmentation of the analgesic effect of ibuprofen by alprazolam was proved for the writhing test at a dose of 30 mg/kg of ibuprofen and alprazolam 1 mg/kg. The reaction time of the combination was significantly prolonged in comparison with ibuprofen alone. The results of the tail-flick test and plantar test were negative. The effect of ibuprofen was not enhanced by alprazolam in tests of acute thermal pain. Our results have demonstrated that the analgesic action of ibuprofen is only weakly enhanced by alprazolam.     

多模式术后镇痛在腹腔镜结肠手术中的应用

目的:理论上联合使用不同机制镇痛药较镇痛药单独使用镇痛效果更完善,在妇科、骨科等手术中已有结论;笔者观察比较腹腔镜结肠手术术使用单一止痛药及联合使用不同机制镇痛药在术后镇痛的效果以及各自不良反应的发生率。方法:择期腹腔镜结肠手术患者90例,随机分为3组,每组30例。A组使用地佐辛+氟比洛酚酯行术后镇痛为多模式镇痛组;B组使用地佐辛行术后镇痛;C组使用氟比洛酚酯行术后镇痛。记录每组术后4、8、12、24 h视觉模糊评分(VAS)及术后不良反应包括嗜睡、躁动、恶心呕吐的发生率。结果:A组术后4 h、8 h的VAS评分低于B、C两组,差异有显著性,A组无嗜睡及躁动发生,发生呕吐1例,不良反应发生率A组低于B、C两组,差异有显著性。结论:地佐辛+氟比洛酚酯联合用药可安全有效应用于腹腔镜结肠手术术后镇痛,是一种有效的多模式术后镇痛方式,在减弱疼痛的放大效应及对中枢神经的作用两方面起效,因而较单独使用地佐辛及氟比洛酚酯有更好的镇痛效果,且不良反应低于单独使用地佐辛及氟比洛酚酯。     

Analgesic efficacy and safety of paracetamol-codeine combinations versus paracetamol alone: a systematic review.

OBJECTIVES--To assess whether adding codeine to paracetamol has an additive analgesic effect; to assess the safety of paracetamol-codeine combinations versus paracetamol alone. DESIGN--Systematic literature review with meta-analysis, methodological quality of published trials being scored by means of 13 predefined criteria. TRIALS--24 of 29 trials that met the inclusion criteria. Models studied in the trials were postsurgical pain (21), postpartum pain (one), osteoarthritic pain (one), and experimentally induced pain (one). INTERVENTIONS--Dosages ranged from 400 to 1000 mg paracetamol and 10 to 60 mg codeine. MAIN OUTCOME MEASURES--The sum pain intensity difference (efficacy analysis) and the proportion of patients reporting a side effect (safety analysis). RESULTS--Most trials were considered of good to very good quality. Only the single dose studies could be combined for analysis of analgesic efficacy. Pooled efficacy results indicated that codeine added to paracetamol provided a 5% increase in analgesia on the sum pain intensity difference. This effect was comparable to the difference in analgesic effect between codeine and placebo. The cumulative incidence of side effects with each treatment was comparable in the single dose trials. In the multidose studies a significantly higher proportion of side effects occurred with paracetamol-codeine preparations. CONCLUSION--The difference is analgesic effect between paracetamol-codeine combinations and paracetamol alone was small but statistically significant. In the multidose studies the proportion of patients reporting a side effect was significantly higher with paracetamol-codeine combinations. For occasional pain relief a paracetamol-codeine combination might be appropriate but repeated use increases the occurrence of side effects.     

Determining Pain Detection and Tolerance Thresholds Using an Integrated,Multi-Modal Pain Task Battery

Human pain models are useful in the assessing the analgesic effect of drugs, providing information about a drug''s pharmacology and identify potentially suitable therapeutic populations. The need to use a comprehensive battery of pain models is highlighted by studies whereby only a single pain model, thought to relate to the clinical situation, demonstrates lack of efficacy. No single experimental model can mimic the complex nature of clinical pain. The integrated, multi-modal pain task battery presented here encompasses the electrical stimulation task, pressure stimulation task, cold pressor task, the UVB inflammatory model which includes a thermal task and a paradigm for inhibitory conditioned pain modulation. These human pain models have been tested for predicative validity and reliability both in their own right and in combination, and can be used repeatedly, quickly, in short succession, with minimum burden for the subject and with a modest quantity of equipment. This allows a drug to be fully characterized and profiled for analgesic effect which is especially useful for drugs with a novel or untested mechanism of action.     

Quantitative analysis of the ultrasonic vocalization responses elicited in adjuvant-induced arthritic rats for screening analgesic drugs

Adjuvant-induced arthritic (AIA) rats have been developed as a chronic pain model to evaluate the effects of analgesic drugs. The purpose of the present study was to examine whether there is dose-dependent inhibition of the emission of ultrasonic vocalization (USV) responses by analgesic drugs in AIA rats. It was demonstrated that morphine (1.25-5.0 mg/kg, s.c.) and ketoprofen (2.5-10.0 mg/kg, s.c.) dose-dependently inhibit USV responses. These results suggest that the USV responses elicited in AIA rats are useful for the quantitative evaluation of analgesic drugs.     

不同浓度沙利度胺对大鼠慢性坐骨神经缩窄模型的镇痛效果及机制

目的:比较不同剂量沙利度胺对大鼠慢性坐骨神经缩窄(chronic sciatic nerve constriction,CCI)的镇痛效果及可能机制。方法:将50只大鼠随机分为S组、C组、L组、M组及H组,S组作为假手术组,其余四组建立CCI模型,术后分别用20 mg/kg、50mg/kg、100 mg/kg沙利度胺处理L组、M组、H组。于术后第1、2、3、4周测量和比较各组大鼠机械性痛阈与热痛阈,采用蛋白质印迹法(Western blot)及实时荧光定量PCR(Q-PCR)检测各组大鼠肿瘤坏死因子受体(TNFR)的mRNA和蛋白表达,并分析沙利度胺浓度与TNFR mRNA相对表达的相关性。结果:S组术前术后的机械性痛阈与热痛阈均无明显改变(P0.05),其余四组术后痛阈均较术前明显下降(P0.05);C组术后第4周时机械性痛阈明显升高(P0.05),而术后其他时间点的机械性痛阈与热痛阈无明显差异(P0.05);L组、M组、H组术后机械性痛阈、热痛阈随时间的延长呈上升趋势,差异有统计学意义(P0.05)。术后,C组机械性痛阈与热痛阈对比S组明显降低(P=0.000),亦显著低于L组(P=0.000);而不同剂量组机械性痛阈、热痛阈相比,H组高于M组(P=0.000),M组高于L组(P=0.000)。相对于C组,L组、M组、H组术后第4周TNFR1 mRNA及蛋白相对含量显著下降(P0.05),其中H组下降最为明显,M组次之。Pearson相关性分析结果显示:沙利度胺浓度的增加与TNFR1表达水平的升高呈明显负相关关系(r=-0.497,P=0.036)。结论:沙利度胺可能通过影响TNFR表达水平对大鼠慢性坐骨神经缩窄发挥镇痛效应,其镇痛效应随剂量增加而加强,有望作为神经病理性疼痛的辅助镇痛药物之一。     

Microwave-induced and pharmacological suppression of somatic pain under conditions of the formalin test in mice

We examined pain-related behavioral reactions and non-pain behavioral manifestations in mice under conditions of the formalin test. Levels of analgesia induced by i.p. injections of analgin, microwave irradiation of an antinociceptive acupuncture point (AP), E-36, or combined application of the above factors were measured. The duration of the pain behavioral reaction (licking of the injured limb) decreased due to irradiation of the AP with microwaves and to injection of 8.3 mg/kg analgin by 24.3% and 53.8%, on average, respectively. Combination of injection of analgin in a smaller dose (4.2 mg/kg) and microwave irradiation of the AP suppressed manifestations of the pain behavioral reaction by 43.4%. Thus, combination of pharmacologically induced analgesia with the action of microwaves on the antinociceptive AP allows one to significantly decrease the doses of analgesic preparations necessary to provide a full-level analgesic effect; in such a way, side effects of the respective drugs can be weakened. Neirofiziologiya/Neurophysiology, Vol. 38, No. 1, pp. 46–51, January–February, 2006.     

Effect of multiple dosing on the analgesic action of diflunisal in rats

This investigation was designed to compare the analgesic effect of the initial dose of a repetitively dosed non-narcotic analgesic with the analgesic effect of a subsequent dose given 3 days later. To exclude gradual drug accumulation as a variable, the first ("loading") dose was larger than the maintenance doses. Male Sprague-Dawley rats received 100 mg/kg diflunisal i.v. as the first dose and 70 or 75 mg/kg every 12 hours thereafter. The analgesic effect of the first and seventh doses was determined as the pain threshold (voltage) upon electrical stimulation of the tail every 15 to 30 minutes from the third to the ninth hour after dosing. Blood samples for drug assay were obtained at 3 and 9 hours. A control group received injections of solvent for 6 doses and 100 mg/kg diflunisal as the seventh dose. There were no statistically significant differences between the area under the total or free (unbound) drug concentration versus time curves of the first and seventh dose but the average analgesic effect (area under the voltage increase versus time) of the seventh dose was only 28 percent that of the first dose. The areas under the drug concentration and analgesic effect versus time curves of the diflunisal dose given as the seventh injection to the control rats were similar to those produced by the first dose given to the multiple dosed rats. The results of this investigation show that the analgesic effect of a non-narcotic drug decreases substantially during repeated dosing in an animal model of experimental pain. This change in pharmacologic response has the characteristics of functional rather than pharmacokinetic tolerance in that there was no change in the drug concentration profile with time and no effect of the manipulations as such (i.e., repeated pain threshold determinations and blood withdrawals) on diflunisal-induced analgesia. These observations may have important implications for the evaluation and use of non-narcotic analgesics in the management of clinical pain.     

Differences in response to anaesthetics and analgesics between inbred rat strains

Differences in response to analgesic and anaesthetic drugs can partly be attributed to variations in the genetic background of experimental animals. This study was carried out to determine differences in the response of inbred rat strains to a selection of analgesics and drugs used in anaesthetic protocols. A cross between the most contrasting strains can then be phenotyped in future studies in order to localize quantitative trait loci (QTLs) involved in analgesic/anaesthetic drug sensitivity. Eight inbred strains (n = 6 rats/strain) were selected for the study: the pigmented ACI, BN and COP strains and the albino F344, LEW, SHR, WAG and WKY strains. Each rat was injected intravenously with two analgesics (buprenorphine 0.05 mg/kg and nalbuphine 1 mg/kg) and three drugs used in anaesthetic protocols (propofol 25 mg/kg, medetomidine 50 microg/kg and ketamine 10 mg/kg), respectively, using a crossover design. Analgesic responses were assessed using an analgesiometric procedure. The sleep time of the rat and, where applicable, the interval between injection and loss of righting reflex were used to determine the anaesthetic response. Six out of eight strains responded significantly different from each other to the analgesic effect of buprenorphine with the ACI strain as hyper-responder. The tail withdrawal latency at 55 degrees C of the F344 and WKY rats using buprenorphine was not significantly different from baseline tail withdrawal latencies. In this study, all strains were non-responsive to the analgesic effects of nalbuphine. The response to all three drugs used in anaesthetic protocols differed significantly among the strains. The F344 and BN strains were relatively resistant to the sedative effects of medetomidine. Use of ketamine was abandoned in the ACI and BN strains when the first two animals of both strains died soon after induction. With all three drugs the sleep time of albino rats was significantly longer compared with that of the pigmented ones. We conclude that the results from this study can be used in future studies where QTLs for the sensitivity to anaesthetic/analgesic drugs are localized.     

Examination of the interaction between peripheral diclofenac and gabapentin on the 5% formalin test in rats

It has been shown that the association of diclofenac with other analgesic agents can increase its antinociceptive activity, allowing the use of lower doses and thus limiting side effects. Therefore, the aim of the present study was to examine the possible pharmacological interaction between diclofenac and gabapentin at the peripheral level in the rat using the 5% formalin test and isobolographic analysis. Diclofenac, gabapentin or a fixed-dose ratio diclofenac-gabapentin combination were administrated locally in the formalin-injured paw and the antinociceptive effect was evaluated using the 5% formalin test. All treatments produced a dose-dependent antinociceptive effect. ED30 values were estimated for the individual drugs and an isobologram was constructed. The derived theoretical ED30 for the diclofenac-gabapentin combination was 597.5+/-87.5 microg/paw, being significantly higher than the actually observed experimental value, 170.9+/-26.07 microg/paw. These results correspond to a synergistic interaction between diclofenac and gabapentin at the peripheral level, potency being about three times higher with regard to that expected from the addition of the effects of the individual drugs. Data suggest that low doses of the diclofenac-gabapentin combination can interact synergistically at the peripheral level and therefore this drug association may represent a therapeutic advantage for the clinical treatment of inflammatory pain.     

Objective assessment of antianginal treatment: a double-blind comparison of propranolol,nifedipine, and their combination.

In a double-blind clinical trial the antianginal effects of nifedipine (30 and 60 mg/day) and propranolol 240 and 480 mg/day) and a combination of both drugs were compared with those of placebo in 16 patients with severe exertional angina pectoris. Response to treatment was assessed by the objective criteria of 16-point precordial exercise mapping and 48-hour ambulatory electrocardiographic monitoring and subjectively by analysis of patients'' daily diaries of episodes of angina and consumption of glyceryl trintrate. The incidence of pain and consumption of glyceryl trinitrate were significantly decreased by each drug compared with placebo, and the combination produced a further significant improvement. Objectively the total area and amount of ST depression on the precordial exercise map and the total number of episodes of ST depression detected on ambulatory monitoring confirmed the efficacy of each treatment regimen; the combination was significantly better than either drug alone (p <0.005). The objective methods permitted greater separation of treatment efficacy and showed reliably that the combination of propranolol and nifedipine was significantly better than either drug alone. Thus this combination is a safe and effective form of treatment for angina.     

Antidepressant-like effects of tramadol and other central analgesics with activity on monoamines reuptake,in helpless rats

Affective states are regulated mainly by serotonin and noradrenaline. However the opioid system has been also related to antidepressant-induced mood improvement, and the mu-opioid receptor has been involved in affective responses to a sustained painful stimulus. Similarly, antidepressant drugs induce an antinociceptive effect via both the monoaminergic and opioid systems, probably involving sensorial and affective dimensions of pain. The aim of this study was to test three opiate analgesics, which also inhibit monoamine reuptake, in the learned helplessness model of depression in rats. Helpless rats receiving (+/-)tramadol (10, 20 mg/Kg) or (-)methadone (2, 4 mg/Kg) showed a decreased number of failures to avoid or escape aversive stimulus (shock) in both the second and the third daily sessions, compared with controls. Rats receiving levorphanol (0.5, 1 mg/Kg) showed a decreased number of such failures in the third session. The number of crossings in the intertrial interval (ITI) was not significantly modified by (+/-)tramadol or (-)methadone. Levorphanol enhanced ITI crosses at 1 mg/Kg. These results, together with other clinical and experimental data, suggest that analgesics with monoaminergic properties improve mood and that this effect may account for their analgesic effect in regulating the affective dimension of pain. From this, it seems probable that the analgesic effect of opiates could be induced by adding together the attenuation produced of both the sensorial and the affective dimensions of pain.     

Carbamazepine Potentiates the Effectiveness of Morphine in a Rodent Model of Neuropathic Pain

Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G) which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4) may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV) current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG), we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS) and over 35% of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ), a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI) model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p.) were observed in TNI rodents at post-injury day (PID) 7–14 and absent at PID21–28, while administration of CBZ (10 mg/kg, i.p.) alone failed to produce anti-nociceptive effects at any time following TNI (PID 7–28). In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a potential therapeutic use of morphine and CBZ as a combinational treatment for neuropathic pain.