Behavioral and pharmacological characterization of a distal peripheral nerve injury in the rat

Previous rat neuropathic pain models have utilized peripheral nerve injuries that damage a significant proportion of large nerves such as the sciatic nerve or its divisions. Injuries that lead to neuropathic pain in humans may involve the peripheral extremities. The current study evaluated the behavioral effects of injury to the plantar nerves in the rat (distal nerve injury-DNI). A delayed onset of hypersensitivity to an innocuous mechanical stimulus was observed following cutting of the left plantar nerves, whereas mechanical hypersensitivity developed more rapidly in rats with either an injury near the sciatic nerve trunk (chronic constriction injury (CCI), spared nerve injury (SNI)) or a spinal nerve root (spinal nerve ligation (SNL). Similar to other nerve injury pain models, rats with injured plantar nerves also developed an early onset and persistent sensitivity to a cooling stimulus. The effects of morphine, gabapentin and imipramine on mechanical and cold hypersensitivity were evaluated in rats with a DNI, CCI and SNI. In all three models, morphine dose-dependently suppressed mechanical and cold hypersensitivity, whereas gabapentin only suppressed mechanical hypersensitivity. Imipramine had no effect on either cold or mechanical hypersensitivity in any of the nerve-injured rats. The pharmacological data suggest that the underlying basis of neuropathic pain may be similar irrespective of the site of nerve injury.     

Actions of intrathecal omega-conotoxins CVID,GVIA, MVIIA,and morphine in acute and neuropathic pain in the rat

Agents which decrease conductance of N-type voltage-gated Ca(2+) channels have been shown to attenuate measures of neuropathic pain in animal models and to provide symptom relief in humans. The omega-conotoxins have demonstrated efficacy but have a low therapeutic index. We have investigated the effects of a new omega-conotoxin, CVID (AM-336), and compared them with omega-conotoxin GVIA (SNX-124), omega-conotoxin MVIIA (SNX-111) and morphine in a spinal nerve ligation model of neuropathic pain in the rat. The ED(50) (and 95% CI) for attenuation of tactile allodynia by intrathecal administration for omega-conotoxin CVID, GVIA, MVIIA and morphine was 0.36 (0.27-0.48), 0.12 (0.06-0.24), 0.32 (0.23-0.45) and 4.4 (2.9-6.5) microg/kg, respectively. Only morphine significantly prolonged acute tail flick responses (ED(50) 2.3 (1.1-4.9) microg/kg). Of the omega-conotoxins, omega-conotoxin CVID showed the highest ratio of efficacy to behavioural toxicity. These observations show that intrathecal omega-conotoxins are effective in attenuating tactile allodynia in the rat without significantly affecting acute nociceptive responses. Omega-conotoxin CVID had similar potency to omega-conotoxin MVIIA but showed less toxicity in the therapeutic range.     

脊髓谷氨酸转运体1对大鼠坐骨神经慢性压迫损伤及吗啡耐受的影响

为了探讨脊髓谷氨酸转运体1 (GLT-1) 的表达量和活性状态与吗啡耐受和神经源性痛的关系,利用大鼠坐骨神经慢性压迫损伤 (CCI) 模型,以机械性缩足痛阈值 (MWT) 为评估指标,谷氨酸转运体激动剂β内酰胺类抗生素头孢曲松钠为工具药,观察对大鼠机械痛敏和吗啡耐受的影响;以实时定量PCR及Western blotting考察脊髓GLT-1表达水平的变化。结果表明,CCI大鼠在术后1周与对照组相比MWT值下降约80%;CCI大鼠单独使用吗啡产生快速耐受,给药第3天与CCI模型对照组大鼠比较MWT值已无明显差异,脊髓GLT-1表达也明显下调;单独使用头孢曲松钠对痛敏有改善作用,脊髓GLT-1表达明显上调;吗啡伴随头孢曲松钠给药组耐受速度明显减慢,给药6天后MWT值仍保持在较高水平,与CCI吗啡耐受组比较有显著性差异,GLT-1表达明显上调。因此,脊髓GLT-1活性变化与神经源性痛及吗啡耐受的形成密切相关,促进GLT-1功能可显著延缓吗啡耐受与痛敏形成。     

Pharmacologic investigation of the mechanism underlying cold allodynia using a new cold plate procedure in rats with chronic constriction injuries

Cold allodynia is a frequent clinical symptom of patients with neuropathic pain. Despite numerous studies of cold allodynia, using animal models of neuropathic pain, little is known about its underlying mechanisms. This study was performed to establish a method for the pharmacologic evaluation of cold allodynia using several analgesics in a chronic constriction injury (CCI) rat model of neuropathic pain. Compared with the results obtained before the CCI operation, the CCI rats placed on a cork plate at 20 degrees C exhibited a slight change in the paw withdrawal latency because of the mechanical stimulus mediated by the injured paw touching the plate. By contrast, there was a significant reduction in the paw withdrawal latency on a cold metal plate compared with that on the cork plate after the CCI surgery, with the maximum decrease occurring on postoperative day 7. This reduction is thought to specifically reflect cold-induced pain behavior. In addition, both na?ve and CCI rats showed behavioral changes at 5 and 0 degrees C, but not at 10 degrees C or higher. Interestingly, a subcutaneous morphine dose of 6 mg/kg completely inhibited cold allodynia induced at 10 degrees C on postoperative day 7. Under this condition, both the sodium channel blocker mexiletine (10 and 30 mg/kg, subcutaneously) and the calcium channel alpha2delta subunit blocker pregabalin (30 and 100 mg/kg, orally) significantly suppressed cold allodynia. Additionally, both resiniferatoxin (0.3 mg/kg, subcutaneously), an ultrapotent analog of capsaicin that desensitizes C fibers, and the VR1 channel antagonist N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide (10 and 30 mg/kg, orally) significantly prolonged the paw withdrawal latency. In conclusion, our data suggest that the activation of C fibers mediates cold allodynia.     

Guggulipid of Commiphora mukul,with antiallodynic and antihyperalgesic activities in both sciatic nerve and spinal nerve ligation models of neuropathic pain

Abstract

Context: Guggulipid is a neutral fraction of ethyl acetate extract of gum resin of the tree Commiphora mukul Engl. (Burseraceae) and used in Ayurvedic medicine for treatment of neurological disorders.

Objectives: The present study was undertaken to assess the antiallodynic and antihyperalgesic activities of guggulipid in rats.

Materials and methods: The screening study included the CCI and L5–L6 SNL models of neuropathic pain. Guggulipid (100 and 50?mg/kg) or saline was administered intraperitoneally in a blinded, randomized manner from postoperative day (POD) 7 to 13. Paw withdrawal duration (PWD) to spontaneous pain, chemical allodynia and mechanical hyperalgesia and paw withdrawal latency (PWL) to mechanical allodynia and thermal hyperalgesia were tested before surgery, before and after guggulipid or saline administration (from POD7 to 13) and after the withdrawal of treatment (from POD14 to 20).

Results: The activity profiles of the different doses of guggulipid were found to vary with time. In CCI rats, guggulipid (100 and 50?mg/kg) significantly (p?<?0.05) reduced the spontaneous pain, mechanical allodynia and mechanical and thermal hyperalgesia responses and the LD₅₀ of guggulipid was 1600?mg/kg. In SNL rats, both doses of guggulipid were found to be ineffective in reversing the spontaneous pain but showing antiallodynic and antihyperalgesic activity.

Discussion and conclusion: The results demonstrated that guggulipid produce antinociception in the peripheral nerve injury (CCI and SNL) models of neuropathic pain. The underlying mechanisms are expected to be modulating microglial activation occurring due to peripheral nerve injury.     

Altered antinociceptive efficacy of tramadol over time in rats with painful peripheral neuropathy

Pain due to peripheral nerve injury or disease is a dynamic process, such that the mechanism that underlies it alters over time. Tramadol has been reported to be analgesic in clinical neuropathic pain, with varying levels of efficacy due to a patient population that has had neuropathic pain for a wide range of time. In order to address and examine the issue, the antinociceptive efficacy of tramadol over time was tested in rats with a chronic constriction injury (CCI) of the left sciatic nerve. Rats developed a robust hind paw hypersensitivity to innocuous mechanical stimulation ipsilateral to CCI surgery. Subcutaneous injection of tramadol in rats two weeks after CCI surgery dose-dependently attenuated mechanical hypersensitivity, which was abolished with the mu-opioid receptor antagonist naloxone but not the alpha(2)-adrenoceptor antagonist yohimbine. Systemic tramadol also attenuated mechanical hypersensitivity four weeks after CCI surgery, but the efficacy significantly diminished at this time point. In addition, the effect of tramadol at this later time point could be reduced with yohimbine as well as naloxone. These data demonstrate that the efficacy of tramadol depends in part on the duration of nerve injury-evoked nociception, and that its antinociceptive mechanism changes over time. Alteration in antinociceptive mechanism over time may explain the inconsistency in efficacy of this and other analgesic drugs in chronic pain patients.     

Effects of koumine, an alkaloid of Gelsemium elegans Benth., on inflammatory and neuropathic pain models and possible mechanism with allopregnanolone

Crude alkaloidal extraction from Gelsemium elegans Benth. produces analgesic property. However, its clinical utility has been obstructed by its narrow therapeutic index. Here, we investigated the potential of koumine, a monomer of Gelsemium alkaloids, to reduce both inflammatory and neuropathic pain. Interestingly, allopregnanolone, a neurosteroid, appeared to mediate the reduction of neuropathic pain. The potential anti-inflammatory pain effects of koumine were evaluated by acetic acid-, formalin- and complete Freund's adjuvant (CFA) -induced nociceptive behaviors in mice. Chronic constriction injury (CCI) and L5 spinal nerve ligation (L5 SNL), inducing thermal hyperalgesia and mechanical allodynia in rats, were used to test whether repeated treatment of koumine ameliorated neuropathic pain. Finally, we explored if koumine altered the level of neurosteroids in rat spinal cord of CCI neuropathy using liquid chromatography-tandem mass spectrometry. Koumine dose-dependently reduced the acetic acid-induced writhes and formalin-induced licking/biting time of Phase II in mice. Repeated administrations of koumine also dose-dependently reversed the CFA-, CCI- and L5 SNL-induced thermal hyperalgesia, as well as, CCI- and L5 SNL-induced mechanical allodynia in rats. The level of allopregnanolone, but not pregnenolone, in the L5-6 spinal cord was elevated by repeated treatment of koumine in CCI-induced neuropathic rats. These results demonstrate that koumine has a significant analgesic effect in rodent behavioral models of inflammatory and neuropathic pain, and that the reduction in neuropathic pain may be associated with the upregulation of allopregnanolone in the spinal cord.     

Ethosuximide reduces allodynia and hyperalgesia and potentiates morphine effects in the chronic constriction injury model of neuropathic pain

Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system and treatment of neuropathic pain remains a challenge. The purpose of the present study was to examine the effect of ethosuximide, an anti-epileptic and relatively selective T-type calcium blocker and morphine, a prototypical opioid in the behavioral responses following the chronic constriction injury (CCI) model of neuropathic pain. Experiments were performed on eight groups (n=8) of male Sprague-Dawley rats (230-280 g). The animals were injected with saline, ethosuximide (100, 200, 300 mg/kg), morphine (4 mg/kg), and a combination of morphine (4 mg/kg) plus ethosuximide (100mg/kg, i.p.). The cold-and mechano-allodynia and thermal hyperalgesia were measured prior to surgery (the day 0) and 3, 5, 7, 14 and 21 days post surgery. Ethosuximide and morphine significantly decreased cold and mechano allodynia and thermal hyperalgesia. However, the co-administration of both drugs seems to be more effective than the ethosuximide or morphine alone on cold and mechano allodynia and thermal hyperalgesia .Our results suggest that ethosuximide block tactile and thermal hypersensitivity after the CCI model, also, ethosuximide potentiates the analgesic effects of morphine in neuropathic pain conditions and behavioral responses.     

Anti-nociception is selectively enhanced by parallel inhibition of multiple subtypes of monoamine transporters in rat models of persistent and neuropathic pain

Rationale Neuropathic pain is characterised by hyperexcitability within nociceptive pathways that manifests behaviourally as allodynia and hyperalgesia and remains difficult to treat with standard analgesics. However, antidepressants have shown reasonable preclinical and clinical anti-nociceptive efficacy against signs and symptoms of neuropathic pain. Objectives To ascertain whether inhibition of serotonin (5-HT) and/or noradrenaline (NA) and/or dopamine (DA) re-uptake preferentially mediates superior anti-nociception in preclinical pain models. Methods The 5-HT re-uptake inhibitor fluoxetine (3–30 mg/kg), the NA re-uptake inhibitor reboxetine (3–30 mg/kg), the dual 5-HT and NA re-uptake inhibitor venlafaxine (3–100 mg/kg) and the dual DA and NA re-uptake inhibitor bupropion (3–30 mg/kg) were tested after intraperitoneal administration in rat models of acute, persistent and neuropathic pain. Results Reboxetine and venlafaxine dose-dependently attenuated second-phase flinching in the formalin test; fluoxetine attenuated flinching only at the highest dose tested, whereas bupropion was ineffective. In the chronic constriction injury (CCI) and spinal nerve ligation models of neuropathic pain, hindpaw mechanical allodynia was significantly attenuated by fluoxetine and particularly by bupropion. Reboxetine and venlafaxine were completely ineffective. In contrast, reboxetine and venlafaxine reversed thermal hyperalgesia in CCI rats, whereas bupropion and fluoxetine were either minimally effective or ineffective. Fluoxetine, reboxetine and venlafaxine transiently increased the tail-flick latency in uninjured animals. Anti-nociceptive doses of drugs had no effect on motor function. Conclusions Combined re-uptake inhibition of 5-HT and NA appears to confer a greater degree of anti-nociception in animal models of experimental pain than single mechanism of action inhibitors. The selective attenuation of mechanical allodynia by bupropion suggests that the additional re-uptake of DA may further augment 5-HT/NA re-uptake mediated anti-nociception after nerve injury.     

Pharmacological characterisation of place escape/avoidance behaviour in the rat chronic constriction injury model of neuropathic pain

Rationale Classical pain tests performed in animals routinely measure evoked nociceptive behaviours. These almost exclusively reflect sensory processing of nociceptive transmission, although a recently described place escape/avoidance paradigm may be used to selectively assess affective pain processing. Objective To establish if drugs with proven analgesic efficacy selectively attenuate sensory-discriminative or affective-motivational aspects of nociceptive processing. Methods The μ-opioid receptor agonist morphine, the anti-epileptic gabapentin, the anti-depressant duloxetine, the 5HT_1A receptor agonist 8-OH-DPAT, the GABA_A receptor agonist gaboxadol and the mixed cannabinoid receptor agonist WIN55,212-2 were tested after systemic administration in the chronic constriction injury (CCI) model of neuropathic pain. For the place escape/avoidance paradigm, CCI rats had free access between the ‘non-aversive’ dark and ‘aversive’ light side of an enclosed chamber. Either the injured or non-injured hindpaw was routinely stimulated if the rat was in the dark or light area, respectively. Escape/avoidance behaviour was defined as a shift from the dark to the light area. Mechanical allodynia and hyperalgesia were determined prior to and following escape/avoidance testing. Results Morphine (3 and 6 mg/kg), gabapentin (50 and 100 mg/kg), duloxetine (10 and 30 mg/kg) and 8-OH-DPAT (0.1 and 0.5 mg/kg) attenuated the time spent by CCI rats in the light area; gaboxadol (1 and 3 mg/kg) and WIN55,212-2 (0.3 and 1 mg/kg) were ineffective. Only gabapentin and 8-OH-DPAT attenuated mechanical nociceptive behaviours at non-sedative doses. Conclusions The place escape/avoidance paradigm may enable discrimination between selected drug classes on distinct components of sensory and affective pain processing in rats with neuropathic pain.     

Minocycline can delay the development of morphine tolerance,but cannot reverse existing tolerance in the maintenance period of neuropathic pain in rats

Neuropathic pain is a challenge for physicians and basic science researchers, because it often does not respond to routine treatment. The administration of morphine has been considered one of the effective recommended treatments, but its wide application is limited because of the development of antinociceptive tolerance. In general, basic science studies focus on neuropathic pain and morphine tolerance separately. However, we tried to investigate the effect of microglial activation on morphine tolerance in spinal nerve ligation (SNL) rats during the maintenance period of neuropathic pain. This study produced the following results. The morphine tolerance model in neuropathic pain was established by repeated administration of morphine twice daily (10 mg/kg s.c) in the maintenance period of SNL rats. Minocycline, the microglial activation inhibitor, was given once daily (30 mg/kg, i.p.) at different time‐points. The CD11b protein level was measured by western blot to monitor microglial activation. Rats’ mechanical allodynia was assessed using the 50% paw withdrawal threshold, and the tail antinociception was determined using the percentage of the maximal possible antinociceptive effect. First, the repeated administration of morphine induced the development of antinociceptive tolerance during the maintenance period of neuropathic pain. Second, during the development of morphine tolerance, microglial activation, which is related to the analgesic effect of morphine, decreased in the first few days, but this pattern was reversed in the following days with the development of morphine tolerance. Third, the repeated administration of minocycline, a microglial activation inhibitor, did not influence the antinociceptive effect of a single dose of morphine. Fourth, the pre‐administration of minocycline can delay the development of morphine tolerance, but repeated minocycline administration cannot reverse existing morphine tolerance. We concluded that microglial activation contributes to the morphine tolerance of SNL rats in the maintenance period of neuropathic pain, and that minocycline delays the development of morphine tolerance, but does not reverse existing morphine tolerance during the maintenance period of neuropathic pain in rats. These findings might be useful for clinical pain management.     

虎杖提取物对神经病理性疼痛模型大鼠的镇痛作用研究

目的：研究虎杖提取物对神经病理性疼痛模型大鼠的镇痛作用,并探讨其作用机制。方法雄性SD大鼠,随机分为对照组和坐骨神经缩狭模型（chronic construction injury, CCI）组。CCI术后14 d,应用Von Frey法测定机械刺激缩足反射阈值（mechanical withdrawal threshold, MWT）,观察口服不同剂量的虎杖提取物对CCI大鼠机械性痛觉超敏的影响。并考察不同剂量虎杖提取物对CCI大鼠脊髓p-ERK、p-P38水平及小胶质细胞活化的影响。结果虎杖提取物可明显升高CCI大鼠术侧的MWT值（P〈0.05）,而对正常大鼠的MWT值没有显著影响（P〉0.05）。同时虎杖提取物可显著抑制CCI模型大鼠脊髓ERK和p38的磷酸化,并显著抑制IBA-1表达增加。结论虎杖提取物对CCI诱导的机械性痛觉超敏具有显著性的抑制作用,且镇痛作用维持时间长于吗啡,其机制可能是通过抑制脊髓水平ERK和p38的磷酸化,及通过抑制小胶质细胞活化而实现。     

Role of bovine adrenal medulla 22 (BAM22) in the pathogenesis of neuropathic pain in rats with spinal nerve ligation

The opioid peptide bovine adrenal medulla 22 (BAM22) is a cleavage product of proenkephalin and has been shown to be involved in inflammatory pain and morphine tolerance. This study was designed to investigate a role of BAM22 in neuropathic pain. L5 spinal nerve ligation (SNL) significantly reduced BAM22-immunoreactivity in small-sized neurons and depleted IB4 binding in injured L5 dorsal root ganglia (DRG) compared to sham rats. Double labeling study showed that the expression of BAM22-immunoreactivity was decreased mainly in IB4 neurons in the neighboring intact L4 and L6 DRGs following SNL. The nerve injury dramatically increased sensitivity of hindpaw to mechanical stimulation. Intrathecal (i.t.) administration of BAM22 on day 10 post-SNL attenuated mechanical allodynia in a dose-dependent manner (3-30 nmol) and the effect lasted for up to 90 min. Similar treatment with morphine at a dose of 30 nmol produced a mild and brief inhibition on pain hypersensitivity. Furthermore, i.t. administration of 30 nmol of BAM22 suppressed SNL-induced upregulation of interleukin-1β (IL-1β) in the spinal dorsal horn. The present study suggests that the reduction of BAM22 expression in small-sized neurons in both injured and the adjacent DRGs may contribute to pain hypersensitivity in peripheral nerve injury as a result of loss of inhibition of IL-1β upregulation in the spinal dorsal horn. Our results support the hypothesis that a reduction of antinociceptive activity loses the counteraction against activity of pronociceptive mediators, enhancing pain hypersensitivity following peripheral nerve injury.     

Knock down of the alpha 5 nicotinic acetylcholine receptor in spinal nerve-ligated rats alleviates mechanical allodynia

Nicotinic acetylcholine receptor (nAChR) agonists are known to alleviate neuropathic and inflammatory pain via activation of a heterogeneous population of receptors. However, the function of nAChRs in the maintenance of neuropathic pain is not known. Spinal nerve ligation (SNL) increases the spinal expression of the alpha5 nAChR subunit ipsilateral to injury. The alpha5 subunit is unique because it modifies numerous characteristics of existing functional nAChRs, but it does not form functional nAChRs when expressed alone or with beta nicotinic subunits. Because there are no alpha5 subunit selective ligands, we used antisense oligonucleotides (ODNs) to assess the contribution of the alpha5 subunit to the maintenance of mechanical allodynia following SNL. Intrathecal antisense oligonucleotides were administered to SNL rats after the development of mechanical allodynia (10-12 days post-SNL). I.t. antisense specifically reduced alpha5 immunoreactivity (alpha5-IR) by 50-70% in the outer laminae of the dorsal horn and moderately alleviated mechanical allodynia. Furthermore, using the phosphorylation of cAMP response element-binding protein (pCREB) as a general marker of neuronal activation, a significant increase in pCREB immunoreactivity was observed in SNL rats. Treatment of SNL rats with alpha5-antisense significantly reduced pCREB immunoreactivity. These results suggest that the increased expression of the alpha5 nAChR subunit following SNL contributes to spinal CREB phosphorylation and the maintenance of mechanical allodynia.     

Pentoxifylline decreases allodynia and hyperalgesia in a rat model of neuropathic pain

BACKGROUND AND THE PURPOSE OF THE STUDY: Pentoxifylline (PTX) is a non-specific cytokite pain in several animal models and humans. However, long-term therapeutic effects of PTX on neuropathic pain in a rat model of chronic constriction injury (CCI) are not completely clear. This study was conducted to examine the effect of long-term administration of PTX on neuropathic pain in rats. METHODS : Neuropathic pain was induced by sciatic nerve ligation using of CCI model in rats. Rats were randomly assigned into sham, CCI-saline treated, and CCI-PTX treated (30 or 60 mg/kg ip) groups. PTX or saline administered at 30 min before CCI and daily for 14 days post-CCI. At the days of 3, 7, 11 and 14 following CCI, by using standard methods effects of thermal hyperalgesia, thermal and mechanical allodynia in all groups were examined using the standard methods. RESULTS : The CCI-saline treated group showed a significant increase in mechanical and thermal allodynia, and thermal hyperalgesia as compared with the sham group in the tested days. Administration of the higher dose of PTX (60 mg/kg/day), but not the lower dose (30 mg/kg/day) significantly reduced mechanical and thermal allodynia, as compared with the CCI-saline treated group on days of 3, 7, 11 and 14 (all P values<0.001). Also, both doses of PTX significantly reduced thermal hyperalgesia as compared with the CCI-saline treated group on these days (all P values<0.001). CONCLUSION : Results of this study show that chronic administration of PTX reduces the neuropathic pain in a rat model of CCI. Thus, this drug may have a therapeutic application in the treatment and management of neuropathic pain in humans.     

Microinjection of morphine into thalamic nucleus submedius depresses bee venom-induced inflammatory pain in the rat

Previous studies have provided evidence of the existence of a pain modulatory feedback pathway consisting of thalamic nucleus submedius (Sm)-ventrolateral orbital cortex-periaqueductal grey pathway, which is activated during acute pain and leads to depression of transmission of nociceptive information in the spinal dorsal horn. The aim of this study was to test the hypothesis that morphine microinjection into the Sm decreased spontaneous pain and bilateral thermal hyperalgesia, as well as ipsilateral mechanical allodynia, induced by subcutaneous injections of bee venom into the rat hind paw. Morphine (1.0, 2.5 or 5.0 microg in 0.5 microL) injected into the Sm, contralateral to the bee venom-injected paw, depressed spontaneous nociceptive behaviour in a dose-dependent manner. Furthermore, morphine significantly decreased bilateral thermal hyperalgesia and ipsilateral mechanical allodynia 2 h after bee venom injection. These morphine-induced effects were antagonized by 1.0 microg naloxone (an opioid antagonist) microinjected into the Sm 5 min before morphine administration. The results provided further support for the important role of the Sm and Sm-opioid receptors in inhibiting nociceptive behaviour and indicated for the first time that Sm opioid receptors were also effective in inhibiting the hypersensitivity provoked by bee venom-induced inflammation.     

Post-injury repeated administrations of minocycline improve the antinociceptive effect of morphine in chronic constriction injury model of neuropathic pain in rat

It is confirmed that pharmacological attenuation of glial cells can alleviate neuropathic pain by lowering proinflammatory cytokine expression. The present study tries to confirm that post-injury administration of glia inhibitor, minocycline, can attenuate the neuropathic pain symptoms and improves the efficacy of morphine anti-nociception in chronic constriction injury (CCI). Male Wistar rats (230-270 g) underwent surgery for induction CCI model of neuropathy. For assessment of the thermal hyperalgesia and mechanical allodynia after CCI induction, morphine (2.5, 5, 7.5, 10 and 15 mg/kg; s.c.) and saline were administered on post-operative days (PODs) 0, 6 and 14. Hargreaves and Von-Frey tests were performed before and 30 min after morphine administration, respectively. The results showed significant decrease in antinociceptive effect of morphine on POD 6 compared to POD 0 only at the dose of 5 mg/kg. On the other hand, on POD 14 the antinociceptive effect of morphine (5, 7.5, 10 and 15 mg/kg) significantly decreased in comparison with POD 0. In another set of experiments, animals received minocycline (10, 20 and 40 mg/kg; i.p.) for eight days from POD 6 to 13 and then the antinociceptive effect of single dose of morphine 5 mg/kg was tested on POD 14. Behavioral tests showed that minocycline (40 mg/kg) could effectively attenuate the thermal hyperalgesia and mechanical allodynia on POD 13. Moreover, minocycline (40, 20 mg/kg) improved the anti-hyperalgesic, and minocycline (40 mg/kg) improved the anti-allodynic effects of morphine 5 mg/kg on POD 14. It seems that the reduction of antinociceptive effect of morphine after CCI may be mediated through glia activation. Modulation of glial activity by minocycline can attenuate CCI-induced neuropathic pain. It is also shown that repeated post-injury administration of minocycline improves the antinociceptive effect of morphine in neuropathic pain.     

The combined predictive capacity of rat models of algogen-induced and neuropathic hypersensitivity to clinically used analgesics varies with nociceptive endpoint and consideration of locomotor function

Different neurobiological mechanism(s) might contribute to evoked and non-evoked pains and to limited translational drug discovery efforts. Other variables including the pain model and sensory testing method used, dose/route/preadministration time of compound(s), lack of adverse effect profiling and level of observer experience might also contribute. With these points in mind, we tested three mechanistically distinct analgesics in rat models of algogen-induced and neuropathic pain. In chronic constriction injury (CCI) rats evoked hindpaw mechanical hypersensitivity and spontaneous weight bearing deficits developed quickly and persisted for at least 3 weeks post-injury. In contrast, evoked cold hypersensitivity, or movement-associated behavioural deficits (rotarod, beam-walking) were less manifested or dissipated rapidly post-injury. Mechanical hypersensitivity was dose-dependently reversed by morphine (3-10 mg/kg, s.c.) and gabapentin (50-200 mg/kg, i.p.). Weight bearing deficits and cold hypersensitivity were reversed only by high doses of each drug. Surprisingly, duloxetine (10-60 mg/kg, s.c.) was largely ineffective in neuropathic rats although it partially reduced formalin-induced spontaneous nocifensive behaviours; especially during interphase, a period associated with activation of descending monoaminergic inhibition. Morphine and gabapentin markedly attenuated second phase formalin- and in addition capsaicin-induced nocifensive behaviours; indicative of effects on central sensitization and nociceptor hyperexcitability mechanisms. Only gabapentin consistently attenuated nociceptive behaviours at a dose that did not impair exploratory locomotor behaviour in naïve rats. Accordingly, this comparative analysis indicates that the pharmacological sensitivity of evoked and non-evoked pain indices does not necessarily correlate within models, perhaps reflecting differing underlying mechanisms. Conversely, the pharmacological specificity of non-evoked pain indices to selected drugs was conserved across models indicative of similar underlying mechanisms enduring in the face of differing aetiology. Finally, although the predictive capacity of these models was largely unaffected by observer-related experience, it was putatively compromised when adverse event profiling of each drug was considered in parallel.     

Preventive and Alleviative Effect of Tramadol on Neuropathic Pain in Rats: Roles of α2-Adrenoceptors and Spinal Astrocytes

The acute analgesic effect of tramadol has been extensively investigated; however, its long-term effect on neuropathic pain has not been well clarified. In this study, we examined the effects of repeated administration of tramadol on partial sciatic nerve ligation–induced neuropathic pain in rats. Each drug was administered once daily from 0 – 6 days (preventive effect) or 7 – 14 days (alleviative effect) after the surgery. Mechanical allodynia was evaluated just before (preventive or alleviative effect) and 1 h after (analgesic effect) drug administration. Like morphine, first administration of tramadol (20 mg/kg) showed an acute analgesic effect on the developed mechanical allodynia, which was diminished by naloxone. Like amitriptyline, repeated administration of tramadol showed preventive and alleviative effects on the mechanical allodynia that was diminished by yohimbine, but not naloxone. The alleviative effects of tramadol lasted even after drug cessation or in the presence of yohimbine. Repeated administration of tramadol increased the dopamine β-hydroxylase immunoreactivity in the spinal cord. Furthermore, tramadol inhibited the nerve ligation–induced activation of spinal astrocytes, which was reduced by yohimbine. These results suggest that tramadol has both μ-opioid receptor–mediated acute analgesic and α₂-adrenoceptor–mediated preventive and alleviative effects on neuropathic pain, and the latter is due to α₂-adrenoceptor–mediated inhibition of astrocytic activation.