Milnacipran is active in models of irritable bowel syndrome and abdominal visceral pain in rodents

The role of antidepressants in the treatment of visceral pain has not been extensively examined. Milnacipran, a serotonin/noradrenalin reuptake inhibitor, has recently been approved in the USA for fibromyalgia, a chronic pathology characterized by diffused/chronic musculoskeletal pain, and a high prevalence of irritable bowel syndrome. Here, we determined its antinociceptive efficacy in two visceral pain tests in rodents: the acetic acid-induced writhing model in mice and the butyrate/colonic distension assay in rats, a model of irritable bowel syndrome. Acute milnacipran (5-40 mg/kgi.p.) significantly and dose-dependently reduced writhing (72.2 ± 3.2 versus 17.0 ± 4.1 writhes at 40 mg/kg). Following repeated administration (40 m/kgi.p. for 5 days), milnacipran preserved its ability to significantly reduce writhing (76 ± 8.3 versus 21.1 ± 6.7 writhes). Similarly, in the butyrate model, acute milnacipran (17.5 and 35 mg/kg, i.p.) significantly and dose-dependently increased cramps induction thresholds (from 45.7 ± 5.7 to 66.3 ± 4.8 and 75.6 ± 2.9 mm Hg, for 17.5 and 35 mg/kg, respectively) and reduced the number of cramps (from 3.0 ± 0.8 to 1.2 ± 0.8 and 0.3 ± 0.3 following inflation of an intra-rectal balloon. To summarise, milnacipran was efficacious in the writhing test, after acute and semi-chronic administration. This effect was confirmed after acute administration in a more specific model of colonic hypersensitivity induced by butyrate. This suggests that milnacipran has potential clinical application in the treatment of visceral pain, such as in irritable bowel syndrome, highly co-morbid with fibromyalgia.     

Purine-mediated signalling in pain and visceral perception

Receptor subtypes for purines have been identified in a variety of tissues, increasing interest in the roles of purine-mediated signalling in pathophysiological processes. Growing evidence supports the involvement of one of the purinoceptor subtypes, P2X3, in nociception. In this article, recent studies of purine-mediated nociception and visceral pain will be discussed. Furthermore, a novel hypothesis is proposed for purine-mediated mechanosensory transduction where ATP released during distension from epithelial cells lining tubes (such as ureter and gut) and sacs (such as the bladder) acts on P2X3 receptors on a subepithelial nerve plexus to initiate impulses that are relayed via the spinal cord to pain centres in the brain.     

Mechanisms of acute visceral pain.

Acute visceral pain is dull, aching, ill-defined, badly localized and often referred to remote areas of the body. These properties indicate that the representation of internal organs within the CNS is very imprecise. There is evidence for the existence of specific visceral nociceptors in some viscera and for the existence of non-specific receptors in other internal organs. Some visceral receptors are 'silent' in normal viscera but become active following acute injury or inflammation of the internal organ that they innervate. The number of nociceptive afferent fibres in viscera is very small but these few nociceptive afferents can excite many second order neurones in the spinal cord which in turn generate extensive divergence within the CNS, sometimes involving supraspinal loops. Such a divergent input activates several systems--sensory, motor and autonomic--and thus triggers the general reactions that are characteristic of visceral nociception: a diffuse and referred pain, and prolonged autonomic and motor activity.     

Improving the translation of analgesic drugs to the clinic: animal models of neuropathic pain

Neuropathic pain remains an area of considerable unmet clinical need. Research based on preclinical animal models has failed to deliver truly novel treatment options, questioning the predictive value of these models. This review addresses the shortcomings of rodent in vivo models commonly used in the field and highlights approaches which could increase their predictivity, including more clinically relevant assays, outcome measures and animal characteristics. The methodological quality of animal studies also needs to be improved. Low internal validity and incomplete reporting lead to a waste of valuable research resources and animal lives, and ultimately prevent an objective assessment of the true predictivity of in vivo models.     

Peripheral kappa-opioid agonists for visceral pain

Kappa (kappa)-opioid receptor agonists are particularly effective analgesics in experimental models of visceral pain. Their analgesic effects are mediated in the periphery. The molecular targets involved include peripherally located kappa-receptors and possibly, at least for some nonpeptidic kappa-agonists, additional nonopioid molecular targets such as sodium channels located on primary sensory afferents. Overall, these properties are expected to be of therapeutic interest in various visceral pain conditions, including abdominal surgery associated with postoperative pain and ileus, pancreatitis pain, dysmenorrhea, labor pain and functional disorders such as irritable bowel syndrome or dyspepsia. The first kappa-agonists to be developed were brain-penetrating organic small molecules. Their development was eventually discontinued due to central side effects such as sedation and dysphoria attributed to kappa-receptors located behind the blood-brain barrier. New drug discovery programs are now geared towards the design of peripherally-selective kappa-agonists. So far, most of the organic molecule-based peripheral kappa-agonists have achieved limited peripheral selectivity and a practically insufficient therapeutic window to justify full development. These compounds have been used in a small number of clinical pilot studies involving visceral pain. Although encouraging, the clinical data available so far with this class of compounds are too limited and fragmented to fully validate the therapeutic utility of kappa-agonists in visceral pain. Additional clinical studies with safer kappa-agonists (i.e. with higher peripheral selectivity) are still required. The most suitable tools to address this question in the future appear to be the newly discovered class of tetrapeptide-based kappa-agonists, which have shown unprecedented levels of peripheral selectivity.     

雷莫司琼降低幼鼠内脏痛觉敏感性

目的:采用行为学和电生理学评价方法,探讨应用5-羟色胺3(5-HT3)受体拮抗剂雷莫司琼对幼鼠内脏痛觉敏感性影响。方法:新生期反复结直肠刺激(colorectal irritation,CI)建立幼鼠内脏痛觉高敏感性模型。32只SD新生大鼠按2×2析因设计分成4组,每组8只,A1B1组:新生期反复CI,15～21d腹腔注射雷莫司琼;A1B2组:新生期反复CI,15～21d腹腔注射生理盐水;A2B1组:新生期未接受CI,15～21d腹腔注射雷莫司琼;A2B2组:新生期未接受CI,15～21d腹腔注射生理盐水。常规饲养到幼鼠期(6周龄),通过观察幼鼠在不同压力结直肠扩张(colorectaldistension,CRD)刺激后的腹壁撤退反射(AWR)评分、内脏痛阈和腹外斜肌放电测量进行内脏痛觉敏感性评价。结果:幼鼠痛阈受建立内脏痛敏化模型和早期雷莫司琼干预两因素影响。建立内脏痛敏化模型可使幼鼠痛阈降低11.56mm Hg,早期雷莫司琼干预则使幼鼠痛阈提高9.06mm Hg,两者存在交互作用。应用雷莫司琼使AWR评分及腹外斜肌放电幅值降低,对于AWR评分的主效应在各个CRD压力下有统计学意义;对腹外斜肌放电幅值的主效应在各不同CRD压力下亦有统计学意义。结论:应用5-HT3受体拮抗剂雷莫司琼能够降低幼鼠内脏痛觉的高敏感性。     

Caerulein and morphine in a model of visceral pain

Summary In pentobarbital-anaesthetized rats (60 mg/kg, i.p.) renal pelvis distension with a pressure of 80 cm H₂O caused a decline in mean arterial blood pressure. This pressure response, which disappeared rapidly after cessation of the distension, was used to study the effects of analgesic drugs known to be effective in renal colic pain in man.Morphine (0.75 and 1 mg/kg, s.c.) and the decapeptide caerulein (1.6, 4 and 8 g/kg, s.c.) abolished the pressure response. The effects of the largest doses lasted for at least 30 min. Ineffective in this respect were (a) desulphated caerulein (40 g/kg, s.c.) and (b) additional doses of pentobarbital (20 and 40 mg/kg, s.c.). This shows (a) the importance of the sulphated tyrosine (known from previous studies on central effects) and (b) the missing influence of the depth of anaesthesia.Naloxone (0.5 mg/kg, s.c.) abolished the effect of morphine (1 mg/kg, s.c.) but failed to influence that of caerulein (8 g/kg, s.c.). Even a fourfold dose of naloxone (2 mg/kg, s.c.) did not weaken the effect of caerulein. Naloxone, per se, was ineffective. These results suggest different mechanisms of the present effects of morphine and caerulein.It appears that renal pelvis distension in the anaesthetized rat can serve as a model of renal colic.     

ZD7288抑制急性内脏痛大鼠痛觉敏化

观察超极化激活环核苷酸门控阳离子通道（HCN通道）的特异性阻断剂ZD7288对急性内脏痛大鼠痛觉敏化的影响。方法：选用成年雄性SD大鼠,通过结肠内注射1％醋酸1mL,建立急性内脏痛模型;免疫组织化学法检测HCN2在模型大鼠腰骶段背根神经节及胸腰段与腰骶段脊髓背角的表达;通过腹壁撤退反射评分和腹外斜肌放电测量,观察模型大鼠鞘内分别给予50与100nmol／LZD7288后内脏痛觉敏化是否发生改变。结果：HCN2在模型大鼠腰骶段背根神经节及胸腰段与腰骶段脊髓背角的表达均较对照大鼠增强（P〈0．05）。鞘内注射50～100nmol／LZD7288可以剂量依赖性降低急性内脏痛模型大鼠的腹壁撤退反射评分和腹外斜肌放电幅值（P〈0．05）。结论：ZD7288可抑制急性内脏痛大鼠的痛觉敏化,而背根神经节和脊髓的HCN2通道可能在其发病中起作用。     

内脏牵涉痛的研究进展

牵涉痛(Referred pain，RP)是许多疾病的一种常见症状。早在1893年Head就曾较系统地研究了内脏器官疾患时在体表产生的牵涉区域，即Head’s区。对于牵涉痛的机制到目前还不很清楚，形成了几种假说，本文就其可能机制及有关其他方面的研究做一综述。     

甲氧氯普胺镇内脏痛的中枢多巴胺机制

在家兔内脏痛模型上观察了甲氧氯普胺(MCP)的镇痛作用。结果:MCP 8mg·kg~(-1)iv有明显的镇内脏痛作用.该作用可被多巴胺(DA)受体激动剂阿扑吗啡.D_1受体激动剂SKF38393.D_2受体激动剂LY171555 icv所拮抗。应用高效液相色谱—电化学检测法也观察到MCP8 mg·kg~(-1)iv20 min后.脑脊液中DA的代谢产物3-甲氧基-4-羟基苯乙酸明显升高。表明MCP的镇内脏痛作用与阻断脑内DA受体有关.D_1、D_2受体的激活均不利于MCP镇痛。     

Targeting the visceral purinergic system for pain control

Experimental evidence is presented to support the hypothesis that purinergic mechanosensory transduction can initiate visceral pain in urinary bladder, ureter, gut and uterus. In general, physiological reflexes are mediated via P2X3 and P2X2/3 receptors on low threshold sensory fibres, while these receptors on high threshold sensory fibres mediate pain. Potential therapeutic strategies are considered for the treatment of visceral pain in such conditions as renal colic, interstitial cystitis and inflammatory bowel disease by purinergic agents, including P2X3 and P2X2/3 receptor antagonists that are orally bioavailable and stable in vivo and agents that modulate ATP release and breakdown.     

Modulation of visceral pain and inflammation by protease-activated receptors

The gastrointestinal (GI) tract is exposed to a large array of proteases, under both physiological and pathophysiological conditions. The discovery of G protein-coupled receptors activated by proteases, the protease-activated receptors (PARs), has highlighted new signaling functions for proteases in the GI tract, particularly in the domains of inflammation and pain mechanisms. Activation of PARs by selective peptidic agonists in the intestine or the pancreas leads to inflammatory events and changes in visceral nociception, suggesting that PARs could be involved in the modulation of visceral pain and inflammation. PARs are present in most of the cells that are potentially actors in the generation of irritable bowel syndrome (IBS) symptoms. Activation of PARs interferes with several pathophysiological factors that are involved in the generation of IBS symptoms, such as altered motility patterns, inflammatory mediator release, altered epithelial functions (immune, permeability and secretory) and altered visceral nociceptive functions. Although definitive studies using genetically modified animals, and, when available, pharmacological tools, in different IBS and inflammatory models have not yet confirmed a role for PARs in those pathologies, PARs appear as promising targets for therapeutic intervention in visceral pain and inflammation processes.     

神经病理性疼痛动物模型

神经病理性疼痛动物模型的不断发展极大地促进了对神经病理性疼痛机制的研究。但是,目前的动物模型仍有很多缺陷,需要不断地完善,对疼痛的观察方法也需要改进。     

神经病理性疼痛动物模型及其评价

对神经病理性疼痛发病机制的研究大多来源于动物模型；尽管模型还存在不少缺点，但是它为理解和探索人类神经病理性疼痛的发病机制提供了有用的工具。动物模型的缺点是动物无法语言交流，对动物的疼痛测量多基于主观行为反应，比如测量痛敏和异常痛敏。最常用的动物模型包括坐骨神经慢性压迫模型和坐骨神经部分损伤模型等，通过测量神经损伤侧肢体脚爪皮肤的感觉阈值即主要通过测评对热、机械刺激痛敏(hyperalgesia)和冷、触异常痛敏(allodynia)来确定模型是否成功。     

Role of serotonergic and noradrenergic systems in a model of visceral pain

The effects of selective manipulations of activity of the serotonergic and noradrenergic systems were examined in the rat model of visceral pain. It was found that neither p-chlorophenylalanine(p-CPA)- nor N-chloro-ethyl-2,2--bromo-benzylamine(DSP-4)-induced strong and selective depletion of the brain and spinal cord serotonin and noradrenaline, respectively, changed in a significant way rat visceral pain perception. On the other hand, 8-OH-DPAT, a full selective 5-HT1A receptor agonist, prazosin, an alpha1-adrenoceptor antagonist, clonidine, an alpha2-adrenoceptor agonist, and two beta-adrenoceptor antagonists: propranolol and metoprolol, dose-dependently reduced the number of body writhes induced by intraperitoneally administered 2% solution of acetic acid (the writhing test). The results obtained with selective receptor ligands, DSP-4 and p-CPA, indicate that the noradrenergic and serotonergic innervation of the central nervous system contribute in a complex way to the animal behavior in the writhing test. The 5-HT1A receptors and alpha2-adrenoceptors play an inhibitory role in the expression of rat behavior in this model of visceral pain. On the other hand, adrenergic alpha1 and beta1 receptors facilitate the behavioral effects of the irritant agent.     

Effects of pregabalin on visceral pain responses and colonic compliance in rats

Background and purpose:

Pregabalin, which binds to the α₂-δ subunit of voltage-gated calcium channels, increased the threshold for pain during colorectal distension (CRD) in irritable bowel syndrome (IBS) patients. We tested the effects of oral pregabalin on the visceral pain-related viscerosomatic and autonomic cardiovascular responses to CRD and colonic compliance in rats.

Experimental approach:

The activity of the abdominal musculature (viscerosomatic response), monitored by electromyography and intracolonic manometry, and changes in blood pressure and heart rate, monitored by telemetry, were assessed simultaneously in conscious rats during CRD.

Key results:

Pregabalin (10–200 μmol kg⁻¹, p.o.) inhibited dose dependently the viscerosomatic response to phasic, noxious CRD (12 distensions at 80 mm Hg). At 200 μmol kg⁻¹, pregabalin also reduced the increase in blood pressure and heart rate associated with noxious CRD. Moreover, pregabalin (200 μmol kg⁻¹, p.o.) reduced the visceromotor response to ascending phasic CRD (10–80 mm Hg) and significantly increased the threshold pressure for response. During phasic CRD (2–20 mm Hg), pregabalin (200 μmol kg⁻¹, p.o.) increased intracolonic volume, resulting in a shift to the left of the pressure–volume relationship curve, indicative of an increase of compliance.

Conclusions and implications:

Pregabalin reduced the viscerosomatic and autonomic responses associated with CRD-induced visceral pain and increased colonic compliance in rats. These observations confirm the analgesic activity of pregabalin on visceral pain and support the translational value of the CRD model to humans. Ligands for the α₂-δ subunit might represent interesting compounds for the treatment of visceral pain disorders, such as IBS.