Endogenous orphanin FQ: evidence for a role in the modulation of electroacupuncture analgesia and the development of tolerance to analgesia produced by morphine and electroacupuncture

1. Our previous work has demonstrated that exogenously administered orphanin FQ (OFQ) antagonizes morphine analgesia and electroacupuncture analgesia (EAA) in the brain and potentiates morphine analgesia and EAA in the spinal cord of the rat. In the present study we evaluated the role of endogenously released OFQ in the development of tolerance to morphine and electroacupuncture (EA) and the analgesia produced by electroacupuncture, by use of the IgG fraction of an anti-OFQ antibody (OFQ-Ab) microinjected into the rat central nervous system (CNS).
2. EAA was produced by stimulating rats at a frequency of 100 Hz. Rats were classified as either high responders (HR) or low responders (LR) based on the analgesic effects of EA. LRs could be converted into HRs by the intracerebroventricular (i.c.v.) microinjection of OFQ-Ab at both 1 : 1 and 1 : 10 dilutions but not 1 : 100. HRs could be changed into LRs by the intrathecal (i.t.) injection of OFQ-Ab at both 1 : 1 and 1 : 10 dilutions, but not 1 : 100.
3. Acute morphine tolerance was induced in rats by repeated subcutaneous (s.c.) injections of morphine (5 mg  kg, every 2 h) for 16 h. When injected i.c.v. the OFQ-Ab (1 : 1 dilution) had no effect on the development of acute morphine tolerance.
4. Chronic morphine tolerance was produced in rats by repeated injection of morphine (5–60 mg  kg, s.c., 3× a day) for 6 days. I.c.v. injection of OFQ-Ab (1 : 1 dilution) reversed this type of morphine tolerance in rats by 50% (P<0.01).
5. Acute tolerance to the analgesia produced by EA developed after 6 h of continuous (100 Hz, 3mA) stimulation. This tolerance was almost completely reversed by the i.c.v. injection of OFQ-Ab (1 : 1 dilution) (P<0.05).
6. Chronic tolerance to the analgesic effect of EA was produced by repeatedly administering increasing current (1, 2 and 3 mA, each lasting for 10 min, for a total of 30 min) at a frequency of 100 Hz once a day for 6 days. I.c.v. injection of OFQ-Ab (1 : 1 dilution) reversed this kind of tolerance by 50% (P<0.01).
7. Together these results suggest that 100 Hz EA may enhance the release of endogenous OFQ in the CNS of the rat, which in turn may act to antagonize EA-produced analgesia in the brain but potentiate EA produced analgesia in the spinal cord. Therefore, OFQ appears to play an important role in the development of tolerance to the analgesic effects produced by EA.
8. The mechanisms underlying the development of acute morphine tolerance and chronic morphine tolerance appear to be different. Central OFQ may play an important role in the development of tolerance after chronic morphine administration.

     

Neuropharmacological analysis of electroacupuncture analgesia

It was established in experiments on conscious rats using concurrent recording of pain sensitivity and evoked potentials that the leading part in electroacupuncture analgesia is played by endogenous opioid peptides. However, numerous pharmacological substances can alter the level of electroacupuncture analgesis suggesting the participation in its genesis of different mediator cerebral systems. In the animals resistant to acupuncture, administration of morphine did not produce marked analgetic effect.     

The role of descending fibers from the rostral ventromedial medulla in opioid analgesia in rats

There has been controversy as to whether the contribution of descending fibers from the rostral ventromedial medulla to opioid analgesia depends on the nature of the noxious stimulus eliciting pain. In the present study, inactivation of descending fibers by microinjection of muscimol (50 ng) in the rostral ventromedial medulla abolished morphine analgesia in the tail immersion and hot plate tests but decreased morphine analgesia by 60% in the formalin test. Analysis of the dose-response relation for morphine after inactivation of descending fibers revealed that, except for the tail immersion test, high doses of morphine could not overcome the block induced by muscimol. Also, morphine analgesia elicited supraspinally was not detectable when descending fibers were inactivated, suggesting that the analgesic effect of morphine in the brain requires a relay via the rostral ventromedial medulla. The analgesic effect of buprenorphine also depends on the integrity of descending fibers from the rostral ventromedial medulla. The results indicate that descending fibers from the rostral ventromedial medulla are critically important to the analgesic effect of opioids, regardless of the type of noxious stimulation eliciting pain. Residual analgesic effects of opioids after inactivation of descending fibers may be due to peripheral effects in the presence of inflammation.     

Effects of four dopamine agonists on l-tetrahydropalmatine-induced analgesia and electroacupuncture analgesia in rabbits

The effects of icv 4 dopamine (DA) agonists on analgesia caused by iv l-tetrahydropalmatine (THP) 8 mg/kg or by electro-acupuncture (EA) were studied by using the potassium iontophoretic dolorimetry in rabbits. The results showed that both THP-induced analgesia and EA analgesia were markedly attenuated by icv of DA or apomorphine (Apo), 2 mixed D1/D2 agonists. Similar results were obtained when SKF-38393, a selective D1 agonist, was applied. On the contrary, quinpirole hydrochloride (Qui), a selective D2 agonist, was found to enhance the analgesic action of THP or EA. However, DA, Apo, SKF-38393 or Qui per se did not influence the baseline pain threshold. All these observations indicate that functional alterations in DA receptor activities may be involved in THP-induced analgesia and EA analgesia, in which D1 and D2 subtype receptors exert different roles.     

The role of renin-angiotensin system in compound 48/80-induced analgesia in rats

1. The antinociceptive effect of compound 48/80 was reversed by the pretreatment with an angiotensin-converting enzyme (ACE) inhibitor, Hoe 498, in a dose-dependent manner and with a opiate receptor antagonist, naloxone (5.0 mg/kg, s.c.) in rats. 2. The increase of plasma beta-endorphin-like immunoreactivity produced through s.c. administration of compound 48/80 was attenuated by the pretreatment with Hoe 498 but not with naloxone. 3. The present data suggest the possible involvement of renin-angiotensin system in compound 48/80-induced analgesia in rats.     

电针对正常大鼠性发育前后下丘脑GnRH释放调控的影响

目的 观察电针(EA)对不同发育阶段大鼠下丘脑促性腺激素释放激素(GnRH)的影响.方法 218只SD大鼠分为幼年段(JG)、青春发育早期段(EPG)、青春发育后期段(LPG)和成年段(AG);每个年龄段随机分为穴位组(EWA)、非穴位组(ENA)、非特异刺激组(IC)和自然对照组(NC).EWA组选取"百会"、"太溪"、"命门"、"肾俞"穴.3 Hz的EA分别刺激EWA组与ENA组大鼠10 d,每天20 min.10 d后测定所有大鼠下丘脑GnRH mRNA的表达.结果 EPG与LPG中的EWA组大鼠在持续电针后GnRH mRNA的表达明显受到抑制(P＜0.01).结论 持续EA刺激可降低青春发育早期与成熟期大鼠下丘脑GnRH的释放.     

The role of zinc ion in the development of gastric ulcers in rats

The properties of the gastric mucosal barrier and acid output were investigated in zinc deficient rats. A decline in total acid output, a significant diminution in hydrogen and sodium ion fluxes and an increase in gastric lesions suggest a marked breakdown of the gastric mucosal barrier in zinc deficient rats.     

The influence of learning on morphine analgesia and tolerance development in rats tested on the hot plate

The influence of learning on the development of tolerance to the analgesic effect of morphine in rats was examined employing the hot plate procedure. A tested-reinforced (Tr) group and its yoked-control, a tested-non-reinforced (Tnr) group, received identical exposure to the testing procedure; the Tr group was reinforced daily for its behavior on the heated plate whereas the Tnr group was reinforced only on the last day of the experiment. Paired statistical comparisons between these two groups on the last day of the experiment revealed that: 1. premorphine control reaction times on the heated plate were significantly lower in Tr than in Tnr animals; and 2. post-morphine increases in reaction time did not differ between Tr and Tnr animals. It was concluded that whereas some learning does occur in this testing procedure, learning does not influence the behavioral tolerance to morphine which develops in this analgesiometric method. An hypothesis which accommodates this behavioral tolerance and a mechanistic scheme is offered.     

The role of potassium channels in antihistamine analgesia

The effect of the administration of pertussis toxin as well as modulators of different subtypes of K⁺ channels on the antinociception induced by the H₁-antihistamines pyrilamine, diphenhydramine and promethazine was evaluated in the mouse hot plate test. Pretreatment with pertussis toxin (0.25 μg/mouse i.c.v.) prevented pyrilamine, diphenhydramine and promethazine antinociception. The K_ATP channel openers minoxidil and pinacidil potentiated the antinociception produced by the H₁-antihistamines whereas the K_ATP channel blocker gliquidone prevented the anti H₁-induced analgesia. The Ca²⁺-gated K⁺ channel blocker apamin antagonized pyrilamine, diphenhydramine and promethazine analgesia. Pretreatment with an antisense oligonucleotide (aODN) to mKv1.1, a voltage-gated K⁺ channel, at the dose of 3.0 nmol/single i.c.v. injection, never modified the antinociception induced by the H₁-antihistamines in comparison with degenerate oligonucleotide (dODN)-treated mice. At the highest effective doses, none of the drugs used modified animals’ gross behaviour nor impaired motor coordination, as revealed by the rota rod test. The present data demonstrate that both K_ATP and Ca²⁺-gated K⁺ channels, contrary to voltage-gated K⁺ channel Kv1.1, represent an important step in the transduction mechanism underlying central antinociception induced by H₁-antihistamines.     

氛氟拉明加强针刺镇痛时前脑啡肽原mRNA的表达(英文)

目的:研究大鼠脑内前脑啡肽原(PPE)mRNA的变化与5-HT的释放剂芬氟拉明加强针刺镇痛的关系.方法:用原位杂交组织化学法观察PPE mRNA的表达.结果:脊髓背角(Ⅰ,Ⅱ层),中缝大核,中缝背核,中央灰质,脚间核,视前外侧区,杏仁核和尾壳核内的PPEmRNA的含量大量升高(P<0.01,vs NS EA),而在隔外侧区,视前内侧区,下丘脑腹内侧核以及脊髓背角Ⅲ—Ⅳ层的PPE mRNA的水平也有中等程度增高(P<0.05,vs NS EA).但在丘脑却没有明显的变化.结论:PPE mRNA含量在与痛相关的区域里增高,是芬氟拉明加强针效的机制之一.     

大鼠脊髓不同类型阿片受体在介导下丘脑弓状核刺激镇痛中的作用

在轻度麻醉大鼠,电刺激下丘脑弓状核(ARH)大大延长了辐射热甩尾潜伏期,脊髓蛛网膜下腔注射(ith)κ阿片受体阻断剂nor-BNI对大鼠基础痛阈及ARH刺激引起的镇痛效应无明显影响,ithδ阿片受体阻断剂ICI 174864和不可逆的“阿片受体阻断剂β-FNA对基础痛阈仍无影响,但剂量依赖性地减弱了ARH刺激镇痛。结果提示,脊髓内的δ和μ受体参与了ARH对脊髓伤害性反射的下行性抑制。     

Activation of spinal cholecystokinin and neurokinin-1 receptors is associated with the attenuation of intrathecal morphine analgesia following electroacupuncture stimulation in rats

We previously demonstrated that electroacupuncture (EA) stimulation both produced antinociception and attenuated intrathecal (i.t.) morphine analgesia, suggesting that EA is capable of inducing two opposing systems, that is, opioid and anti-opioid mechanisms. This study examined the involvement of cholecystokinin (CCK) in the anti-opioid effects following EA in the spinal cord. EA was applied to commonly used acupoints for antinociception, ST-36 located 5-mm lateral to the anterior tubercle of the tibia, and analgesia was assessed by the hind-paw pressure test in male Sprague-Dawley rats. I.t. administration of CCK (0.01 - 10 microg) attenuated i.t. morphine analgesia (10 microg) dose-dependently. The attenuation of morphine analgesia following EA was reversed by i.t. proglumide, a CCK-receptor antagonist (0.01 microg). CCK-like immunoreactivity was increased in lamina I and II in the dorsal horn, and expression of spinal CCK mRNA increased after EA. Moreover, i.t. pretreatment with the neurokinin-1 (NK1)-receptor antagonist L-703,606 (18 microg) reversed both EA- and CCK-induced attenuation of morphine analgesia. These results suggest that CCK-mediated neural systems in the spinal cord may be involved in the attenuation of morphine analgesia following EA and that substance P-induced activation of NK1 receptors may be responsible for the downstream neuronal transmission of the CCK-mediated neuronal system.     

大鼠伏膈核内多巴胺受体与电针镇痛的关系

目的：研究多巴胺受体拮抗剂左旋四氢巴马汀（ｌ－ＴＨＰ）加强电针镇痛（ＥＡＡ）的原理，阐明中枢神经系统内多巴胺（ＤＡ）系统在ＥＡＡ中的作用，方法：分别将Ｄ１受激动剂ＳＫ＆Ｆ－３８３９３和Ｄ２受体激动剂ｑｕｉｎｐｉｒｏｌｅｈｙｄｒｏｃｈｌｏｒｉｄｅ（Ｑｕｉ）注射入大鼠伏膈核，观察对ＥＡＡ及ｌ－ＴＨＰ加强ＥＡＡ的作用。结果：ＳＫ＆Ｆ－３８３９３（５μｇ，１０μｇ）明显对抗ｌ－ＴＨＰ加强ＥＡＡ的作用，１０