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Combining Human and Rodent Genetics to Identify New Analgesics

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Neuroscience Bulletin 2018年第1期34卷 143-155页

作者： Alban Latremoliere Michael Costigan Kirby Neurobiology Center Boston Children's Hospital and Department of Neurobiology Harvard Medical School Department of Anesthesiology Perioperative and Pain Medicine Boston Children's Hospital

Most attempts at rational development of new Analgesics have failed, in part because chronic pain involves multiple processes that remain poorly understood. To improve translational success, one strategy is to select novel targets for which there is proof of clinical relevance, either genetically through heritable traits, or pharmacolog- ically. Such an approach by definition yields targets with high clinical validity. The biology of these targets can be elucidated in animal models before returning to the patients with a refined therapeutic. For optimal treatment, having biomarkers of drug action available is also a plus. Here we describe a case study in rational drug design： the use of controlled inhibition of peripheral tetrahydrobiopterin （BH4） synthesis to reduce abnormal chronic pain states without altering nociceptive-protective pain. Initially iden- tified in a population of patients with low back pain, the association between BH4 production and chronic pain has been confirmed in more than 12 independent cohorts, through a common haplotype （present in 25% of Cau- casians） of the rate-limiting enzyme for BH4 synthesis, GTP cyclohydrolase 1 （GCH1）. Genetic tools in mice have demonstrated that both injured sensory neurons and activated macrophages engage increased BH4 synthesis to cause chronic pain. GCH1 is an obligate enzyme for de novo BH4 production. Therefore, inhibiting GCH1 activity eliminates all BH4 production, affecting the synthesis of multiple neurotransmitters and signaling molecules and interfering with physiological function. In contrast, target- ing the last enzyme of the BH4 synthesis pathway, sepiapterin reductase （SPR）, allows reduction of patholog- ical BH4 production without completely blocking physio- logical BH4 synthesis. Systemic SPR inhibition in mice has not revealed any safety concerns to date, and available genetic and pharmacologic data suggest similar responses in humans. Finally, because it is present in vivo only when SPR is inhibited, sepiapterin serves as a reliable biomarke

关键词： Chronic pain Genetics Mouse models Tetrahydrobiopterin Sepiapterin reductase Analgesics

Venoms as a source for therapeutics:translating venom peptides into Analgesics

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Venoms as a source for therapeutics:translating venom peptid...

Synthesis and evaluation of peptide-fentanyl analogue conjugates as dualμ/δ-opioid receptor agonists for the treatment of pain

第八届海峡两岸毒理学研讨会

作者：刘中华湖南师范大学生命科学院多肽药物湖南省工程实验室中国毒理学会生物毒素毒理专业委员会中国毒理学会青年委员会

A greatly diverse range of animals,including arachnids,centipedes,cone snails,reptiles,squid,and wasps,have evolved venoms for the purpose of predation or defense.The use of animal venoms for therapeutic purposes has been well established in Chinese,Indian,Greek and Middle Eastern cultures for millennia.Animal venoms are complex cocktails composed of a great diversity of bioactive compounds including proteins,peptides,organic molecules and salts.Studies indicate that animal venoms also bear a great diversity of bioactivities,which is beneficial for the discovery of new substances of pharmacological interest.There are currently six FDA-approved drugs derived from venom peptides or proteins,with a further ten in clinical trials and many more in various stages of preclinical development.Pain afflicts a fifth of the population;there is an urgent need for new analgesic drugs with minimal side effects.Voltage-gated sodium channels（VGSCs）are essential for the initiation and propagation of action potentials in excitable tissues.Considerable in vivo and in vitro studies indicate that VGSCs play a key role in neuropathic and inflammatory pain.Of the nine subtypes of VGSCs identified to date and designated as Navl.1-1.9,Navl.3,1.7,1.8 and 1.9 play specialized roles in nociceptive pathways and are considered ideal targets for the development of analgesic drugs.We identified two venom peptides from spider and snake venoms,respectively.They could specifically inhibit Navl.7 and Navl.8,respectively.Significantly,nanomolar application of both peptides by intramuscular injection could extenuate inflammatory pain on formalin test,abdominal constriction（writhing）test and the spinal nerve model,respectively.The analgesic effects would compare favorably with that of morphine and didn’t associate with obvious side effects even at20-folder higher dose.Therefore,both peptides might be useful candidates for the development of Analgesics.

关键词： venom peptide voltage-gated sodium channels Analgesics

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Chinese Chemical Letters 2022年第8期33卷 4107-4110页

作者： Jing Li Tao Zhang Jialin Sun Fengxia Ren Hongxin Jia Zixing Yu Jingchao Cheng Weiguo Shi State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China School of Chemical Engineering and Technology Tianjin UniversityTianjin 300350China

Novel peptide-fentanyl analogue conjugates were synthesized by the covalent coupling of carfentanyl derivatives to the C-terminus or N-terminus of the conformationally constrained dermorphin tetrapeptide BVD03 via a chemical linker.The carfentanyl-related analogues displayed distinct binding and functional activities atμ/δopioid receptors(MOR/DOR)and antinociceptive effects when conjugated to the peptide.The most potent compound,SW-LJ-11,displayed mixed MOR/DOR agonist properties in the low nanomolar range and significant analgesic efficacy in vivo in four classic mouse models of pain.Interestingly,SW-LJ-11 did not exhibit any physical dependence or respiratory depression,in contrast to an equipotent analgesic dose of morphine or BVD03,indicating that the use of opioid peptide-fentanyl analogue conjugates as dual MOR/DOR agonists may be a promising strategy for obtaining safer opioids.

关键词： Peptide-small molecule conjugates Dual MOR/DOR agonists Lead compound Analgesics Physical dependence

Lipid bound extended release buprenorphine(high and low doses)and sustained release buprenorphine effectively attenuate post-operative hypersensitivity in an incisional pain model in mice(Mus musculus)

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Animal Models and Experimental Medicine 2021年第2期4卷 129-137页

作者： Kaela Navarro Katechan Jampachaisri Monika Huss Cholawat Pacharinsak Department of Comparative Medicine Stanford UniversityStanfordCAUSA Department of Mathematics Naresuan UniversityPhitsanulokThailand

Background:Extended-release buprenorphine(XR)is indicated for pain management in rodents,but little is known about its use in mice.This study aimed to investigate whether high dose XR effectively attenuates post-operative hypersensitivity better than low dose XR in a mouse model of incisional pain.Methods:Mice(n 44)were randomly assigned to 1 of 4 treatment groups:(a)saline(1 ml/kg SC,once);(b)sustained release buprenorphine(Bup-SR,1 mg/kg SC,once);(c)low dose extended-release buprenorphine(XR-lo,3.25 mg/kg SC,once);(d)high dose extended-release buprenorphine(XR-hi,6.5 mg/kg SC,once).On days􀆴1,0(4 hours),1,2,and 3,mechanical and thermal hypersensitivities were evaluated,and plasma buprenorphine concentrations were measured.Results:Mechanical(days 0-2)and thermal(days 0-1)hypersensitivities were ob-served in the saline group.Bup-SR,XR-lo,and XR-hi attenuated mechanical hyper-sensitivity on days 0,1,and 2.None of the treatment groups,except XR-Lo on day 0,attenuated thermal hypersensitivity on days 0 or 1.Plasma buprenorphine concen-tration peaked at 4 hours(day 0)in all treatment groups and remained greater than 1 ng/mL on days 0-2.No abnormal clinical observations or gross pathologic findings were seen in any groups.Conclusion:The results indicate XR-hi did not effectively attenuate post-operative hypersensitivity better than XR-lo.Thus both 3.25 and 6.5 mg/kg XR are recom-mended for attenuating post-operative hypersensitivity for at least up to 48 hours in mice.

关键词： analgesia Analgesics buprenorphine mouse pain management

Effects of Salvia miltiorrhiza Bunge extract and its single components on monosodium urate-induced pain in vivo and lipopolysaccharide-induced inflammation in vitro

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Journal of Traditional Chinese Medicine 2021年第2期41卷 219-226页

作者： FENG Jinghui Set Byeol Kim Hee Jung Lee Su Min Sim Soon Sung Lim Hong Won Suh Department of Pharmacology College of MedicineHallym UniversityChuncheon 200-702South Korea Department of Food Sciences and Nutrition College of NaturalHealthand Life SciencesHallym UniversityChuncheon 200-702Republic of

OBJECTIVE:To investigate the possible antinociceptive effects of Salvia(S.)miltiorrhiza Bunge and its single components in monosodium urate(MSU)-induced pain model in mice and lipopolysaccharide(LPS)-induced inflammation model in RAW264.7 cells.METHODS:Pretreatment of S.miltiorrhiza Bunge extract(from 1 to 50μg/mL)concentration-dependently attenuated LPS-induced nitric oxide(NO)release.The extract of S.miltiorrhiza Bunge(50 or 100 mg/kg)also caused reversals of decreased threshold for pain in the MSU-treated group as measured by Von-Frey test.Furthermore,we assessed the antinociceptive and anti-inflammatory properties of the active single components from S.miltiorrhiza Bunge such as 15,16-dihydrotanshinoneⅠ,tanshinoneⅠ,cryptotanshinone,miltirone,tanshinoneⅡA,and salvianolic acid B.Some of them showed an anti-inflammatory effect in LPS-induced NO release model and an antinociceptive effect in MSU-treated pain model.RESULTS:Our results suggest that S.miltiorrhiza Bunge extract may exert anti-inflammatory effect by reducing LPS-induced NO release and an antinociceptive property in MSU-treated pain model.Especially,tanshinoneⅡA,miltirone,cryptotanshinone,and 15,16-dihydrotanshinoneⅠ,not only appear to be responsible for LPS-induced NO release induced by S.miltiorrhiza Bunge,but also in the production of S.miltiorrhiza Bunge extract-induced antinociception in MSU-treated pain model.CONCLUSION:Therefore,the analgesic and anti-inflammatory property of S.miltiorrhiza Bunge indicate it as a therapeutic potential candidate for the treatment of pain and inflammation.

关键词： Salvia miltiorrhiza lipopolysaccharides nitric oxide inflammation Analgesics

Immune responses in fatalities involving opioids

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Forensic Sciences Research 2019年第2期4卷 195-198页

作者： Henry J.Carson Linn County Medical Examiner’s Office Cedar RapidsIAUSA

In some cases of fatalities involving opioid use,the concentrations of detected opioids are not in the toxic range.Immune reactions can be triggered by opioid use,suggesting that immune response may be a factor in these cases.Autopsy cases from 2002–2012 were reviewed.Persons with physical,microscopic or serum evidence of allergic reactions and opioid use at autopsy were compared to persons who used opioids but had no such signs.Overall,49 persons were identified who had used opioids,of which five had evidence of immune response.A medical history of asthma was significantly more common in persons with signs of immune response(P=0.0244)and fatality(P=0.0085)compared to normals.A history of asthma is suggestive of susceptibility to immunologic reactions to opioids,and correlates strongly with the cause of death.

关键词： Forensic medicine allergy drug Analgesics opioid asthma drug overdose tryptases

Influence of the quickness and duration of De Qi on the analgesic effect of acupuncture in primary dysmenorrhea patients with a cold and dampness stagnation pattern

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Journal of Traditional Chinese Medicine 2019年第2期39卷 258-266页

作者： Hu Nijuan Ma Liangxiao Wang Pei Wu Guiwen Zhao Minyi Hu Shangqing Sun Junjun Wang Yafeng Zhang Zhuang Zhu Jiang School of Acupuncture Moxibustion and Tuina Beijing University of Chinese Medicine the Key Unit of State Administration of Traditional Chines Medicine Evaluation of Characteristic Acupuncture Therapy

OBJECTIVE: To investigate the influence of the quickness and duration of De Qi(or Qi arrival) on the analgesic effect of acupuncture in primary dysmenorrhea patients with a cold and dampness stagnation pattern.METHODS: Sixty-eight patients were randomly assigned to the De Qi group(deep needling with thick needles and manipulation, n = 17) or the non-De Qi group(shallow needling with thin needles and no manipulation, n = 51). Both groups underwent needling at Sanyinjiao(SP 6) for 30 min.The visual analogue scale was used to measure the degree of menstrual pain, and the Acupuncture De Qi Clinical Assessment Scale was used to assess De Qi. Only data from patients who experienced actual De Qi were included in the analysis.RESULTS: Thirty-nine patients experienced actual De Qi. Patients who experienced actual De Qi in the De Qi group(n = 14) felt De Qi more rapidly(P =0.028) and for a longer duration(P = 0.04) than patients who experienced actual De Qi in the non-De Qi group(n = 25). Both groups showed a reduction in the visual analogue scale score for pain after treatment. The analgesic effect did not significantly differ between the two groups. The occurrence time of De Qi showed a significant negative correlation with pain reduction at 20 and 30 min after needle removal(P < 0.05). There was no correlation between the duration of De Qi and the therapeutic effect.CONCLUSION: In primary dysmenorrhea patients with a cold and dampness stagnation pattern,quicker onset of De Qi when needling Sanyinjiao(SP 6) achieves a better analgesic outcome. However, a longer duration of De Qi does not affect the degree of analgesia. Compared with minimal acupuncture, active acupuncture stimulation achieves a more rapid onset and longer duration of De Qi.

关键词： Dysmenorrhea Cold-dampness Acupuncture Analgesics Arrival of Qi Duration Occurrence time

Qualitative phytochemical screening and evaluation of anti-inflammatory, analgesic and antipyretic activities of Microcos paniculata barks and fruits

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Journal of Integrative Medicine 2015年第3期13卷 173-184页

作者： Md.Abdullah Aziz Department of Pharmacy Stamford University Bangladesh

OBJECTIVE： The main objectives of this study were to qualitatively evaluate the profile of phytochemical constituents present in methanolic extract of Microcos paniculata bark（BME） and fruit（FME）, as well as to evaluate their anti-inflammatory, analgesic and antipyretic activities.METHODS： Phytochemical constituents of BME and FME were determined by different qualitative tests such as Molisch’s test, Fehling’s test, alkaloid test, frothing test, Fe Cl3 test, alkali test, Salkowski’s test and Baljet test. The anti-inflammatory, analgesic and antipyretic activities of the extracts were evaluated through proteinase-inhibitory assay, xylene-induced ear edema test, cotton pellet-induced granuloma formation in mice, formalin test, acetic acid-induced writhing test, tail immersion test and Brewer’s yeastinduced pyrexia in mice.RESULTS： M. paniculata extracts revealed the presence of carbohydrates, alkaloids, saponins, tannins, flavonoids and triterpenoids. All of the extracts showed significant（P〈0.05, vs aspirin group） proteinaseinhibitory activity, whereas the highest effect elicited by plant extracts was exhibited by the BME（75.94% proteinase inhibition activity） with a half-maximal inhibitory concentration（IC50） of 61.31 μg/m L. Each extract at the doses of 200 and 400 mg/kg body weight showed significant（P〈0.05, vs control） percentage inhibition of ear edema and granuloma formation. These extracts significantly（P〈0.05, vs control） reduced the paw licking and abdominal writhing of mice. In addition, BME 400 mg/kg, and FME at 200 and 400 mg/kg showed significant（P〈0.05, vs control） analgesic activities at 60 min in the tail immersion test. Again, the significant（P〈0.05, vs control） post-treatment antipyretic activities were found by BME 200 and 400 mg/kg and FME 400 mg/kg respectively.CONCLUSION： Study results indicate that M. paniculata may provide a source of plant compounds with anti-inflammatory, analgesic and antipyretic activities.

关键词： phytochemical screening agents,anti-inflammatory Analgesics antipyretic agents Microcos paniculata medicine,herbal

Dexmededomidine in pediatric unilateral internal inguinal ring ligation

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World Journal of Clinical Cases 2022年第21期10卷 7376-7385页

作者： Guang Liu Ling Zhang Hui-Se Wang Yi Lin Hong-Quan Jin Xiao-Dan Wang Wei-Na Qiao Ya-Tao Zhang Jiao-Qian Sun Zhi-Na Liu Department of Anesthesiology Baoding Children's HospitalBaoding 071000Hebei ProvinceChina

BACKGROUND Safe and effective analgesia strategy remains one of the priorities for pediatric inguinal hernia treatment.AIM To explore safety and efficacy of dexmededomidine monotherapy for postoperative analgesia in children who received laparoscopic unilateral internal inguinal ring ligation.METHODS This randomized single-center controlled trial included 390 children(aged 1-3 years,ASA grade I-II),randomly divided into a dexmededomidine group(D group),a dexmededomidine+sufentanil group(DS group),and a sufentanil group(S group).The primary endpoint was percentage of children with the Face,Legs,Activity,Cry,and Consolability(FLACC)score≤3 points 2 h after surgery.RESULTS The comparisons of the FLACC scores at 2,4,6,8,12,and 24 h were not significantly different among the three groups(P>0.05).The sedative effects in the D group were significantly better than those in the S group(P>0.05),but not significantly different from those in the DS group.The incidence of nausea and vomiting was significantly lower in the D group than in the S group and DS group(P>0.05).CONCLUSION Analgesic effects of dexmededomidine monotherapy are comparable to those of sufentanil alone or in combination with dexmededomidine for children who underwent laparoscopic unilateral internal inguinal ring ligation,with better sedative effects and a lower incidence of adverse events.

关键词： Child Dexmededomidine Inguinal hernia Pain management Laparoscopy Analgesics