Expression of brain prolactin releasing peptide (PrRP) changes in the estrous cycle of female rats

The aim of this study was to determine whether spinal cord stimulation (SCS) modulates activity of lumbosacral spinal neurons receiving input from the urinary bladder. Extracellular potentials of L6-S2 spinal neurons were recorded in pentobarbital anesthetized, paralyzed and ventilated male rats. SCS (50 Hz, 0.2 ms, 3-5 min, 90% motor threshold) was applied on the dorsal column of L2-L3 and C1-C2 segments and significantly reduced excitatory responses of 18/25 (72%) and 13/19 (68%) lumbosacral neurons to noxious urinary bladder distension (UBD, > or =1.0 ml, 20 s), respectively. SCS affected spinal neurons with either high- or low-threshold responses to UBD. These results suggested that SCS might have a potential therapeutic effect for patients with hypersensitivity and/or pain of cystitis and other urinary bladder disorders.     

When words are painful: unraveling the mechanisms of the nocebo effect

The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patient's distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinson's disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.     

The absence of endogenous beta-endorphin selectively blocks phosphorylation and desensitization of mu opioid receptors following partial sciatic nerve ligation

Phosphorylation of specific sites in the second intracellular loop and in the C-terminal domain have previously been suggested to cause desensitization and internalization of the mu-opioid receptor (MOP-R). To assess sites of MOP-R phosphorylation in vivo, affinity-purified, phosphoselective antibodies were raised against either phosphothreonine-180 in the second intracellular loop (MOR-P1) or the C-terminal domain of MOP-R containing phosphothreonine-370 and phosphoserine-375 (MOR-P2). We found that MOR-P2-immunoreactivity (IR) was significantly increased within the striatum of wild-type C57BL/6 mice after injection of the agonist fentanyl. Pretreatment with the antagonist naloxone blocked the fentanyl-induced increase. Furthermore, mutant mice lacking MOP-R showed only non-specific nuclear MOR-P2-IR before or after fentanyl treatment, confirming the specificity of the MOR-P2 antibodies. To assess whether MOP-R phosphorylation occurs following endogenous opioid release, we induced chronic neuropathic pain by partial sciatic nerve ligation (pSNL), which caused a significant increase in MOR-P2-IR in the striatum. pSNL also induced signs of mu opioid receptor tolerance demonstrated by a rightward shift in the morphine dose response in the tail withdrawal assay and by a reduction in morphine conditioned place preference (CPP). Mutant mice selectively lacking all forms of the beta-endorphin peptides derived from the proopiomelanocortin (Pomc) gene did not show increased MOR-P2-IR, decreased morphine antinociception, or reduced morphine CPP following pSNL. In contrast gene deletion of either proenkephalin or prodynorphin opioids did not block the effects of pSNL. These results suggest that neuropathic pain caused by pSNL in wild-type mice activates the release of the endogenous opioid beta-endorphin, which subsequently induces MOP-R phosphorylation and opiate tolerance.     

Chemotherapy-evoked painful peripheral neuropathy: analgesic effects of gabapentin and effects on expression of the alpha-2-delta type-1 calcium channel subunit

Chemotherapeutics in the taxane and vinca-alkaloid classes sometimes produce a painful peripheral neuropathy for which there is no validated treatment. Experiments with rat models of paclitaxel- and vincristine-evoked pain suggest that these conditions may not respond to all of the analgesics that have efficacy in other models of painful peripheral neuropathy. We tested gabapentin as a potential analgesic for paclitaxel- and vincristine-evoked pain. We used a repeated dosing paradigm because there are precedents showing that repeated drug exposure may be necessary to demonstrate analgesia in neuropathic pain models. Gabapentin is believed to work via binding to voltage-gated calcium channels that contain the alpha-2-delta type-1 (alpha(2)delta-1) subunit, and the expression of this subunit is known to be increased in some painful peripheral neuropathy models. Thus we also examined whether the paclitaxel-evoked pain syndrome was accompanied by an alpha(2)delta-1 increase, and whether gabapentin had any effect on subunit expression. We found that the paclitaxel- and vincristine-evoked mechano-allodynia and mechano-hyperalgesia were significantly reduced by gabapentin, but only with repeated dosing. Paclitaxel-evoked painful peripheral neuropathy was associated with an increased expression of the alpha(2)delta-1 subunit in the spinal dorsal horn, but not in the dorsal root ganglia. The spinal cord increase was normalized by repeated gabapentin injections. Together, these findings suggest that repeated dosing with gabapentin may be beneficial in patients with chemotherapy-evoked painful peripheral neuropathy and that gabapentin's mechanisms of action may include normalization of the nerve injury-evoked increase in calcium channel alpha(2)delta-1 subunit expression.     

Both GnRH agonist and continuous oral progestin treatments reduce the expression of the tyrosine kinase receptor B and mu-opioid receptor in deep infiltrating endometriosis

BACKGROUND: Deep infiltrating endometriosis (DIE) is commonly associated with severe pain. The pain can be managed successfully with GnRH agonists or continuous progestins. The precise molecular mechanism by which DIE causes pain or why hormonal treatment is effective, however, remains unclear. We recently identified three potential candidate genes that might be involved in DIE pain pathways: tyrosine kinase receptor B (TrKB), mu-opioid receptor (MOR) and serotonin transporter (5HTT). We hypothesized that if these three genes were involved in DIE-associated pain, their expression levels would probably be modulated by GnRH agonist or progestin. In this study, we compared mRNA expression levels of TrKB, MOR and 5HTT in DIE among patients pre-operatively treated with GnRH agonist, progestin or without pre-operative medical treatments. METHODS: The expression levels of TrKB, MOR and 5HTT mRNA in DIE were determined using laser capture microdissection and real-time RT-PCR techniques. RESULTS: The expression levels of TrKB in epithelial cells and MOR in stromal cells from DIE were significantly decreased in patients with pre-operative GnRH agonist or progestin. There was no significant difference in 5HTT expression levels among untreated, GnRH agonist- and progestin-treated patients. CONCLUSION: The expression levels of TrKB and MOR genes in DIE appeared to be modulated by GnRH agonist or progestin. However, the functional roles of TrKB and MOR in DIE remain to be clarified.     

Pain drawings and concepts of pain among patients with "half-body" complaints

OBJECTIVE: To explore main features of pain drawings and concepts about illness in patients seeking help for "half-body" complaints at two primary health care centres in different parts of Sweden. METHODS: A qualitative study of pain-drawings and tape-recorded semi-structured interviews analysed by qualitative methods in 20 patients (4 men, 16 women, aged 37-68 years) from five health centers. Three of them were native Swedes and 17 were foreign-born. RESULTS: All complained of pain in a left (three-fourth) or right (one-fourth) body-half, mainly in front. Some had general pain with a "worse side". Many said they had pain only on the "edges" and outlined the margins on the side of pain, but excluded the "face". Posterior drawings often received a line in the middle dividing the body in lateral halves. Pain was referred to as a "growing" thing - ("It") - that could spread ("jump") to the other side, grow and eventually paralyse them. "It" was believed as caused by body imbalance, natural factors or supernatural forces. CONCLUSION: "Half-body" pain was an expression that in main was used by middle-aged patients to denote an initially superficial and frontal one-sided pain that could spread and become dangerous to their health. PRACTICE IMPLICATIONS: Patients with half-body complaints should be taken seriously and met with respect by doctors and other health care personnel, particularly in cross-cultural consultations.     

Epinephrine potentiates the analgesic and antidepressant effects of amitriptyline as a result of stimulation of the gastric mucosal afferents

Intramuscular amitriptyline in the minimum effective dose causes maximum analgesic and antidepressant effect and significant sedation in rats. Combined injection of amitriptyline with epinephrine in the threshold doses (ineffective if used alone), 1/10 and 1/30 minimum effective doses, respectively, leads to the development of the maximum analgesic and antidepressant effect, but causes no sedative side effect. This potentiation is mediated by stimulation of afferents in the gastric mucosa with epinephrine. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 11, pp. 535–537, November, 2007     

Hospitalization costs and resource allocation in cholecystectomy with use of intravenous versus oral acetaminophen

Objective: To evaluate intravenous (IV) acetaminophen (APAP) vs oral APAP use as adjunctive analgesics in cholecystectomy patients by comparing associated hospital length of stay (LOS), hospital costs, opioid use, and rates of nausea/vomiting, respiratory depression, and bowel obstruction.

Methods: We conducted a retrospective analysis of the Premier Database (January 2012 to September 2015) including cholecystectomy patients who received either IV APAP or oral APAP. Differences in LOS, hospitalization costs, mean daily morphine equivalent dose (MED), and potential opioid-related adverse events were estimated. Multivariable logistic regression was performed for the binary outcomes and instrumental variable regressions, using the quarterly rate of IV APAP use for all hospitalizations by hospital as the instrument in two-stage least squares regressions for continuous outcomes. Models were adjusted for patient demographics, clinical risk factors, and hospital characteristics.

Results: Among 61,017 cholecystectomy patients, 31,133 (51%) received IV APAP. Subjects averaged 51 and 57 years of age, respectively, in the IV and oral APAP cohorts. In the adjusted models, IV APAP was associated with 0.42 days shorter LOS (95% CI?=?–0.58 to –0.27; p?p?p?=?.0005), and lower rates of respiratory depression (odds ratio [OR]?=?0.89, 95% CI?=?0.82–0.97; p?=?.006), and nausea and vomiting (OR?=?0.86, 95% CI?=?0.86–0.86; p?Conclusions: In patients having cholecystectomy, the addition of IV APAP to perioperative pain management is associated with shorter LOS, lower costs, reduced opioid use, and less frequent nausea/vomiting and respiratory depression compared to oral APAP. These findings should be confirmed in a prospective study comparing IV and oral APAP.     

镇痛药物作用靶点的研究现状

疼痛是临床上的常见症状,也是当今困扰人类健康的严重问题之一,而控制疼痛是临床用药的主要方面之一。该文对现阶段已有的镇痛靶点及新型镇痛靶点进行简要的阐述,以期为新型、不良反应小、无耐受性、无成瘾性的镇痛药物的研究和开发,以及临床上的应用提供参考。     

阿霉素减轻坐骨神经慢性缩窄性损伤大鼠的神经病理性疼痛及其机制

目的观察阿霉素(DOX)对坐骨神经慢性缩窄性损伤(CCI)模型大鼠的镇痛作用,并从形态学及组织凋亡蛋白的角度对其机制进行分析。方法将SD大鼠随机分为4组:假手术组(Sham)、CCI模型组(Model)、假手术+阿霉素5 mg·kg^-1组(Sham+DOX)、CCI模型+阿霉素5 mg·kg^-1组(Model+DOX)。造模成功后,各组采用尾静脉注射的方式给药,Sham组和Model组给予等量生理盐水,检测各组大鼠机械痛阈值和热痛阈值。在行为学检测结束后,即手术后d 15取大鼠右侧L4-5DRG,观察DRG细胞形态、超微结构及DOX的分布情况,采用Western blot法测定DRG组织中Bax、Bcl-2、PKCɑ、PKCδ及PKCε的蛋白表达。结果静脉注射DOX可在DRG组织检测到其自发荧光表达。与Sham组相比,Sham+DOX组痛阈值在整个观察期未见差别,而Model组在术后d 7痛阈值明显降低。与Model组相比,Model+DOX组的痛阈值在给药后明显回升,并表现出DRG细胞明显损伤,Bax/Bcl-2升高以及PKCδ、PKCε的蛋白表达量降低等现象。结论 DOX静脉注射可以到达并蓄积于DRG组织,明显减轻CCI大鼠的疼痛反应,这一作用与其降低PKCδ和PKCε的蛋白表达,诱导DRG的凋亡有关。