| 英文摘要 |
The role played by cholecystokinin octapeptide (CCK-8) in the central nervous system (CNS) in antagonizing opioid analgesia. Electrophysiological vs behavioral studies: Results of electrophysiological study in rats supported that of behavioral study to ascertain that the antinociceptive effect of electroacupuncture (EA) can be antagonized by exogenously administered CCK-8 at nanogram doses, and that tolerance to EA analgesia could be reversed by CCK-8 antiserum administered intracerebroventricularly (icv). Since the discharges of the nociceptive neurons in the parafasciculus nucleus do not involve motor component, the results could be regarded as a strong supplement to the previous studies where tail flick was used as the endpoint of nociception. Site of action for CCK-8 to antagonize opioid analgesia: Aside from the periaqueductal gray (PAG) of midbrain, there are at least 2 more nuclei, the nucleus accumbens and the amygdala where microinjection of CCK-8 antagonizes opioid analgesia. Thus, the sites of action for CCK-8 coincide with those of morphine in modulating pain and analgesia. The type of CCK receptor located in the above mentioned nuclei and in the spinal dorsal horn have been characterized by autoradiography technique to be the CCK(subscript B) type. Morphine triggers CCK release: Morphine was found to accelerate the release of CCK8 from the rat spinal cord, an effect which was readily abolished by the opioid antagonist naloxone. The results clearly suggest that CCK indeed serves as a negative feedback control for opioid analgesia. High frequency (100 Hz) EA triggers CCK release: High frequency (100 Hz) EA stimulation was found to be more effective than low frequency (2 Hz) stimulation in releasing CCK-8 from the spinal cord. In accordance with this, CCK antagonist L365, 260 showed a potentiating effect only to the analgesic effect induced by high-, but not low-frequency EA stimulation. CCK(subscript A) vs CCK(subscript B) receptors: CCK(subscript B) receptor antagonist L365, 260 was found to be 40 times more effective than the CCK(subscript A) antagonist devazepide in potentiating EA analgesia and in preventing the development of EA tolerance, implying that it is the CCK(subscript B) receptor which play a cardinal role in antagonizing opioid analgesia. Possible mechanisms underlying the anti-opioid effect of CCK-8 Receptor-receptor interaction: In the studies performed during the period 1987-1989 we had shown that CCK-8 decreased the B(subscript max) of μ-opioid receptor and increased the K(subscript d) of μ-opioid receptor without changing the δ-opioid binding. These findings coincide very well with the pharmacological profile where CCK-8 blocks the analgesia mediated by μ-andη-but not δ-receptors. Further studies revealed that CCK-8 not only suppresses the receptor from binding to opioid agonist, but also prevents the receptor from binding with opioid antagonist ([3H] naloxone) which has no intrinsic activities. It is therefore suggested that a direct receptor-receptor interaction could happen at the plasmic membrane level, although interaction at post-receptor level could not be ruled out by this experiment. Uncoupling of G protein from opioid receptors: It is well known that GTP may cause a dissociation or uncoupling of G protein from opioid receptors thereby reduces the binding capability of opioid receptors in membrane preparation. While both CCK-8 and GTP(subscript γ)S (stable analog of GTP) decreased opioid binding, no further decrease occurred when GTP(subscriptγ)S was used in combination with CCK-8. The results suggest that these two agents may work via the same mechanism of dissociation between receptor and G protein. cAMP is not involved n the anti-opioid effect of CCK-8: This conclusion was derived from two independent findings: (a) the effect of opioids in lowering the intracellular cAMP was not affected by CCK-8, and (b) CCK-8 per se does not affect cAMP level in spinal cord. Inositol triphosphate (IP3) is involved in the anti-opioid effect of CCK-8: CCK-8 caused an increase in intracellular IP3 level of neonatal rat brain cells at concentrations ranging from 0.1 nM to 1.0 nM, but not at higher concentrations. This is in line with the pharmacological findings that an antinociceptive effect occurred only at low (physiological) concentrations but not at higher doses. CCK-8 increases intracellular free calcium level: Three lines of evidence have been obtained. (a) CCK-8 (0.1-1 nM) increased intracellular calcium level in neonatal rat brain cells, even in the calcium-free medium, possibly due to mobilization of intracellular calcium storage by IP3. (b) the effect of morphine (10-1000 nM) in lowering [Ca(superscript 2+)] i in rat brain synaptosomal preparation was reversed by CCK-8 (10-100 nM), an effect mediated by CCK receptor as it could be reversed by CCK receptor antagonist proglumide. (c) CCK-8 (0.3-30 nM) was effective in antagonizing the calcium lowering effect induced by μ-and η-, but not δ-receptors. This is in line with the pharmacological profile that CCK blocked the analgesic effect induced by μ-and μ-, but not by δ-opioid agonist. Protein kinase C (PKC) may participate in anti-opioid mechanisms of CCK-B: A rational outcome of phophoinositide hydrolysis is the production of IP3 as well as diacylglycerol (DAG). We have used TPA to mimic DAG for activating DAG-PKC pathway, and found that icy injection of TPA markedly antagonized opioid analgesia (to be published). Therefore, activation of PKC (which has been known to accelerate Ca(superscript 2+) influx via Ca(superscript 2+) channels) may serve as one of the mechanisms for the anti-opioid effect of CCK-8. The effect of CCK-8 in the control of cardiovascular and immune functions The anti-opioid effect of CCK-8 in cardiovascular control: The depressor effects of opioids can be reversed by CCK-8. Intrathecal injection of CCK-8 augmented hemorrhagic shock, whereas intrathecal injection of CCK antiserum postponed the recovery of blood pressure from hemorrhagic shock. The above mentioned effects of CCK can be readily reversed by the CCK(subscript B) receptor antagonist. The results suggest that like in the neural centers controlling nociception, CCK-8 also plays an anti-opioid effect in neural centers controlling cardiovascular functions. CCK-8 does not show anti-opioid effect at macrophage cells: It is well documented that morphine suppressed the function of macrophages, using the H2O2 releasing activity as an index of macrophage function. CCK-8 showed similar activities as opioids, rather than an antagonistic activity. It is concluded that while CCK-8 shows an anti-opioid effect in the CNS, this may not be regarded as an universal rule for all kinds of cells, at least not in the macrophages in the peripheral blood and in the peritoneal cavity. CCK-B does not show anti-opioid effect at macrophage cells: It is well documented that morphine suppressed the function of macrophages, using the H2O2 releasing activity as an index of macrophage function. CCK-8 showed similar activities as opioids, rather than an antagonistic activity. It is concluded that while CCK-8 shows an anti-opioid effect in the CNS, this may not be regarded as an universal rule for all kinds of cells, at least not in the macrophages in the peripheral blood and in the peritoneal cavity. |
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