Man-Ying Xu

Both endogenous and exogenous ACh plays antinociceptive role in the hippocampus CA1 of rats

Summary.The present study examines the effect of acetylcholine (ACh), muscarinic acetylcholine receptors (mAChRs) agonist pilocarpine and mAChRs antagonist atropine on the pain-evoked response of pain-excited neurons (PEN) and pain-inhibited neurons (PIN) in the hippocampal CA1 of rats. The trains of electric impulses applied to the sciatic nerve were used as noxious stimulation. The discharges of PEN and PIN in the hippocampal CA1 were recorded by glass microelectrode. The results showed that intrahippocampal microinjection of ACh (2 µg/1 µl) or pilocarpine (2 µg/1 µl) decreased the frequency of discharge of PEN, and increased the frequency of discharge of PIN evoked by the noxious stimulation in the hippocampal CA1, while intrahippocampal administration of atropine (0.5 µg/1 µl) produced opposite response. On the basis of the above findings, we can deduce that ACh and mAChRs are involved in the modulation of nociceptive information transmission in the hippocampal CA1.

Cholinergic mechanism involved in the nociceptive modulation of dentate gyrus

Acetylcholine (ACh) causes a wide variety of anti-nociceptive effects. The dentate gyrus (DG) region of the hippocampal formation (HF) has been demonstrated to be involved in nociceptive perception. However, the mechanisms underlying this anti-nociceptive role have not yet been elucidated in the cholinergic pain-related neurons of DG. The electrical activities of pain-related neurons of DG were recorded by a glass microelectrode. Two kinds of pain-related neurons were found: pain-excited neurons (PEN) and pain-inhibited neurons (PIN). The experimental protocol involved intra-DG administration of muscarinic cholinergic receptor (mAChR) agonist or antagonist. Intra-DG microinjection of 1 microl of ACh (0.2 microg/microl) or 1 microl of pilocarpine (0.4 microg/microl) decreased the discharge frequency of PEN and prolonged firing latency, but increased the discharge frequency of PIN and shortened PIN inhibitory duration (ID). Intra-DG administration of 1 microl of atropine (1.0 microg/microl) showed exactly the opposite effects. According to the above experimental results, we can presume that cholinergic pain-related neurons in DG are involved in the modulation of the nociceptive response by affecting the discharge of PEN and PIN.

Noradrenergic mechanism involved in the nociceptive modulation of nociceptive-related neurons in the caudate putamen

Norepinephrine (NE) participates in pain modulation of the central nervous system. The caudate putamen (CPu) is one region of the basal ganglia that has been demonstrated to be involved in nociceptive perception. Our previous work has shown that microinjection of different doses of norepinephrine into the CPu produces opposing effects in the tail-flick latency (TFL) of rats. However, the mechanism of action of NE on the pain-related neurons in the CPu remains unclear. The present study examined the effects of NE and the alpha-adrenoceptor antagonist phentolamine on the pain-evoked response of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the CPu of rats. Trains of electric impulses were used for noxious stimulation, and were applied to the sciatic nerve. The electrical activities of pain-related neurons in the CPu were recorded by a glass microelectrode. The results revealed that intra-CPu microinjection of NE (8microg/2microl) increased evoked firing frequency of PEN and shortened the firing latency, but decreased the evoked firing frequency of PIN and prolonged the inhibitory duration (ID). Intra-CPu administration of phentolamine (4microg/2microl) showed the opposite effects. The above results suggest that NE in the CPu modulates nociception by affecting the baseline firing rates of PENs and PINs.

Morphine dependence changes the role of droperidol on pain-related electric activities in caudate nucleus.

Droperidol causes the blockage of the dopamine receptors in the central nervous system that are involved in pain transmission. However, the mechanism of action of droperidol in pain-related neurons is not clear, and it is still unknown whether opioids are involved in the modulation of this processing. The present study examines the effect of droperidol on the pain-evoked response of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the caudate nucleus (Cd) of rats. The trains of electric impulses applied to the sciatic nerve were used as noxious stimulation. Our results revealed that droperidol decreased the frequency of PEN discharge, and increased the frequency PIN discharge evoked by the noxious stimulation in the Cd of normal rats, while administration of droperidol to morphine-dependent rats produced the opposite response. Those demonstrated that droperidol is involved in the modulation of nociceptive information transmission in Cd, and there were completely opposite responses to painful stimulation between normal and morphine-dependent rats after administration of droperidol.

Microinjection of different doses of norepinephrine into the caudate putamen produces opposing effects in rats.

It has been proven that norepinephrine (NE) regulates antinociception through its action on alpha-adrenoceptors located in brain nuclei, spinal cord, and peripheral organs. However, the supraspinal mechanism of noradrenergic pain modulation is controversial. The present study was aimed at investigating the nociceptive effects induced by injecting different doses of NE and phentolamine into the caudate putamen (CPU) of rats. The thermal pain threshold of the rats was measured by performing a tail-flick test. The tail-flick latency (TFL) was measured at 2-60 min after microinjection of the drugs. Our results revealed that the thermal pain threshold increased (long TFL) after the administration of a low dose of NE (2 microg/2 microl) and decreased (short TFL) after injection of a high dose of NE (8 microg/2 microl). In contrast, the pain threshold decreased after the administration of a low dose of phentolamine (1 microg/2 microl), while it increased after injection of a high dose of phentolamine (4 microg/2 microl). These results indicated that the injection of different doses of NE in the CPU of the rats produced opposite effects on the pain threshold, as determined by the tail-flick tests.

Effect of Inhibition of the Central Nucleus of the Amygdala and Drug Experience on the Regions Underlying Footshock-induced Reinstatement of Morphine Seeking

This study assessed the effect of inhibition of the central nucleus of the amygdala (CeA) and drug experience on brain regions underlying footshock-induced reinstatement of morphine-seeking behaviour in rats. The difference in time spent in two chambers of a place-preference apparatus was used to measure morphine-conditioned place preference. Fos was measured as a marker of neuronal activation in the ventral bed nucleus of the stria terminalis (BNSTv) and ventral tegmental area (VTA). Footshock was found to enhance Fos expression in the BNSTv regardless of drug experience. In the VTA, morphine and footshock had an interactive effect on the increase in Fos expression. Inhibition of the CeA decreased Fos expression in the BNSTv regardless of drug experience, whereas in the VTA this effect only occurred in morphine-treated rats. These results suggest that drug experience has no differential effect on the BNSTv however morphine produces footshock sensitization in the VTA. CeA inhibition modulates the footshock-induced activity of these regions of the brain and attenuates reinstatement of drug seeking behaviour.

Dopamine affects the change of pain-related electrical activity induced by morphine dependence.

Morphine is among the most effective analgesics. However, many evidences suggest that, besides the well-know analgesic activity, repeated opioids treatment can induce some side effects such as dependence, hyperalgesia and tolerance. The mechanism of noxious information transmission in the central nervous system after dependence is not clear. An important neurotransmitter, dopamine (DA) participates not only in the process of opioid dependence but also in pain modulation in the central nervous system. In the present study we observed changes of electrical activities of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the caudate nucleus (Cd) following the development of morphine dependence. We also observed the role of DA on these changes. Our results revealed that both the latency of PEN discharges and the inhibitory duration of PIN discharges decreased, and the net increased values of PEN and PIN discharges increased in the Cd of morphine dependent rats. Those demonstrated that electrical activities of both PENs and PINs increased in morphine dependent rats. DA inhibited the electrical activities of PENs and enhanced those of PINs in morphine dependent rats.

MK-801 changes the role of glutamic acid on modulation of algesia in nucleus accumbens.

Dizocilpine maleate (MK-801) causes the blockage of the glutamic acid (Glu) receptors in the central nervous system that are involved in pain transmission. However, the mechanism of action of MK-801 in pain-related neurons is not clear, and it is still unknown whether Glu is involved in the modulation of this processing. This study examines the effect of MK-801, Glu on the pain-evoked response of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the nucleus accumbens (NAc) of rats. The trains of electric impulses applied to the sciatic nerve were used as noxious stimulation. The electrical activities of PENs or PINs in NAc were recorded by a glass microelectrode. Our results revealed that the lateral ventricle injection of Glu increased the discharged frequency and shortened the discharged latency of PEN, and decreased the discharged frequency and prolonged the discharged inhibitory duration (ID) of PIN in NAc of rats evoked by the noxious stimulation, while intra-NAc administration of MK-801 produced the opposite response. On the basis of above findings we can deduce that Glu, MK-801 and N-methyl-D-aspartate (NMDA) receptor are involved in the modulation of nociceptive information transmission in NAc.

Effect of acetylcholine on pain-related electric activities in hippocampal CA1 area of normal and morphinistic rats.

To examine the effect of acetylcholine (ACh) on the electric activities of pain-excitation neurons (PEN) and pain-inhibitation neurons (PIN) in the hippocampal CA1 area of normal rats or morphinistic rats, and to explore the role of ACh in regulation of pain perception in CA1 area under normal condition and morphine addiction. The trains of electric impulses applied to sciatic nerve were set as noxious stimulation. The discharges of PEN and PIN in the CA1 area were recorded extracellularly by glass microelectrode. We observed the influence of intracerebroventricular (i.c.v.) injection of ACh and atropine on the noxious stimulation-evoked activities of PEN and PIN in the CA1 area. Noxious stimulation enhanced the electric activity of PEN and depressed that of PIN in the CA1 area of both normal and addiction rats. In normal rats, ACh decrease the pain-evoked discharge frequency of PEN, while increased the frequency of PIN. These effects reached the peak value at 4 min after injection of ACh. In morphinistic rats, ACh also inhibited the PEN electric activity and potentialized the PIN electric activity, but the maximum effect appeared at 6 min after administration. The ACh-induced responses were significantly blocked by muscarinic receptor antagonist atropine. Cholinergic neurons and muscarinic receptors in the hippocampal CA1 area are involved in the processing of nociceptive information and they may play an analgesia role in pain modulation. Morphine addiction attenuated the sensitivity of painrelated neurons to the noxious information. 研究 ACh 对正常大鼠和吗啡成瘾大鼠海马CA1 区痛兴奋神经元(pain-excitation neurons, PEN)和痛抑制神经元(pain-inhibitation neurons, PIN)电活动的影响, 进一步探讨ACh对正常和吗啡成瘾状态下CA1区痛觉调制的作用及机制。 电刺激坐骨神经作为伤害性电刺激, 在细胞外用?璃微电极记录CA1区PEN和 PIN 的放电, 观察ACh 对正常大鼠和吗啡成瘾大鼠CA1 区PEN 和PIN 电活动的影响。 伤害性刺激能够增强PEN 的电活动, 而减弱PIN 的电活动。正常大鼠中, ACh 使PEN 的痛诱发放电频率降低, PIN 的放电频率增加; ACh 的作用在注射后4 min 达到峰值。吗啡成瘾大鼠中, ACh 同样也抑制了PEN 的电活动, 兴奋PIN 的电活动, 但是作用的高峰出现在注射后6 min。胆碱能受体拮抗剂阿托品可阻断ACh的作用。 海马CA1 区内的胆碱能神经元和毒蕈碱受体参与了伤害性信息的处理, 并且起到了镇痛作用。吗啡成瘾可以降低CA1区痛反应神经元对伤害性刺激的敏感性。

Modulatory role of glutamic acid on the electrical activities of pain-related neurons in the hippocampal CA3 region

Glutamic acid (Glu) participates in pain modulation of the central nervous system. The CA3 region of the hippocampal formation has been suggested to be involved in nociceptive perception. However, it is unknown whether Glu could modulate the electrical activities of pain-related neurons in the hippocampal CA3 region. The present study aimed to determine the effects of Glu and its receptor antagonist MK-801 in the pain-evoked response of both pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal CA3 region of normal rats. We used a train of electric impulses applied to the sciatic nerve as noxious stimulation. The electrical activities of either PENs or PINs in the hippocampal CA3 region were recorded by a glass microelectrode. The results revealed that intra-CA3 region microinjection of Glu (0.5 μg/1 μl) increased the evoked firing frequency and shortened the firing latency of PEN, while decreased the evoked firing frequency and prolonged the inhibitory duration of PIN in the hippocampal CA3 region of rat evoked by the noxious stimulation. Intra-CA3 region administration of MK-801 (0.25 μg/1 μl) produced the opposite response. These results suggest that Glu and its receptors in hippocampal CA3 region are involved in the modulation of nociceptive information transmission by affecting the electric activities of PENs and PINs.