Intrathecal Substance P-Saporin for the Treatment of Intractable Cancer Pain

Objective To explore the effect of dexmedetomidine combined with morphine in intractable cancer pain with patient-controlled intravenous analgesia (PCIA).Methods Forty patients with intractable cancer pain were divided into experiment group and control group by random digits table method with 40 cases each.Composition of experiment group:morphine 200 mg + dexmedetomidine 1.0 mg + ondansetron 16 mg + 0.9％ sodium chloride.Composition of control group:morphine 200 mg+ ondansetron 16 mg + 0.9％ sodium chloride.Both analgesic fluid volume were 200 ml.The patients in experiment group were administrated 10 min with 0.5 μg/kg dexmedetomidine then received PCIA,the patients in control group were administrated 10 rmin with equal 0.9％ sodium chloride then received PCIA.The visual analogue scale (VAS) score was recorded 2 h before administration and 2,4,8,16,32,48 h after administration.Ramsay sedation score was recorded at all the time points after administration.The press number of patient-controlled analgesia pump and dosage of morphine in 48 h after administration,incidence of side effects (low pressure,bradycardia,respiratory inhibition,nausea and vomiting) were recorded.Results Compared with 2 h before administration,the VAS score was significantly lower at every time point after administration in the 2 groups,there was statistical difference (P ＜ 0.01).The Ramsay sedation score at every time point after administration in experiment group was significantly higher than that in control group,the press number of patient-controlled analgesia pump in 48 h was significantly lower than that in control group [(4.5 ± 2.2) times vs.(18.4 ± 5.4) times],dosage of morphine was significantly lower than that in control group [(90.8 ±7.2) mg vs.(100.5 ± 10.5) mg,the incidence of nausea and vomiting was significantly lower than that in control group,there were statistical differences (P ＜ 0.01).However,there were no significant differences in the incidence of respiratory depression and low pressure between the 2 groups (P ＞ 0.05).Conclusion Dexmedetomidine combined with morphine in the treatment of intractable cancer pain can effectively improve the analgesic effect and sedative effect,reduce the dosage of morphine. Key words: Dexmedetomidine; Morphine; Analgesia,patient-controlled; Pain,intractable

1. The aim of the present study was to examine the role of NK1 and NK2 receptors in the control of mechanical activity of mouse stomach. In this view, the motor effects induced by NK1 and NK2 receptor agonists and antagonists were analyzed, measuring motility as intraluminal pressure changes in mouse-isolated stomach preparations. In parallel, immunohistochemical studies were performed to identify the location of NK1 and NK2 receptors on myenteric neurons and smooth muscle cells. 2. Substance P (SP) induced biphasic effects: a contraction followed by relaxation; neurokinin A (NKA) and [beta-Ala8]-NKA(4-10), selective agonist of NK2 receptors, evoked concentration-dependent contractions, whereas [Sar9, Met(O2)11]-SP, selective agonist of NK1 receptors, induced concentration-dependent relaxation. 3. SR48968, NK2 receptor antagonist, did not modify the spontaneous activity and reduced the contractile effects induced by tachykinins without affecting the relaxation. SR140333, NK1 receptor antagonist, did not modify the spontaneous activity and antagonized the relaxant response to tachykinins, failing to affect the contractile effects. 4. The relaxation to SP or to [Sar9, Met(O2)11]-SP was abolished by tetrodotoxin (TTX) and significantly reduced by N(omega)-nitro-L-arginine methyl ester (L-NAME). 5. NK2-immunoreactivity (NK2-IR) was seen at the level of the smooth muscle cells of both circular and longitudinal muscle layers. NK1-immunoreactive (NK1-IR) neurons were seen in the myenteric ganglia and NK1/nNOS double labeling revealed that some neurons were both NK1-IR and nNOS-IR. 6. These results suggest that, in mouse stomach, NK1 receptors, causing relaxant responses, are present on nitrergic inhibitory myenteric neurons, whereas NK2 receptors, mediating contractile responses, are present at muscular level.

1. Following the recent proposal that the selective agonist septide, ([pGlu6,Pro9]SP(6-11)), acts on a novel tachykinin receptor distinct from the 'classical' NK1 receptor, the aim of the study was to investigate the possible heterogeneity of tachykinin NK1 receptors in the rat urinary bladder. 2. The synthetic tachykinin receptor agonists, septide (pD2 7.87) and [Sar9]substance P (SP) sulphone (pD2 7.64) produced concentration-dependent contractions of the rat isolated urinary bladder. 3. The NK1 receptor antagonists GR82,334, (+/-)-CP96,345, and RP67,580 competitively antagonized (slopes of Schild plot not significantly different from unity) the response to septide with the rank order of potency (pKB values in parentheses): RP 67,580 (7.57) > GR 82,334 (7.01) > (+/-)-CP 96,345 (6.80). The same antagonists were significantly less potent when tested against [Sar9]SP sulphone, while maintaining the same rank order of potency: RP 67,580 (7.00) > GR 82,334 (5.93) > (+/-)-CP 96,345 (< 6). The antagonists did not affect the concentration-response curve to bombesin. 4. To exclude the involvement of the NK2 receptor, a second series of experiments was performed in the presence of the potent nonpeptide NK2 receptor antagonist, SR 48,968. SR 48,968 (1 microM) produced a rightward shift of the concentration-response curve to the NK2 receptor selective agonist, [beta Ala8]neurokinin A (NKA) (4-10). SR 48,968 did not significantly modify the response to SP, NKA, neurokinin B (NKB), neuropeptide K (NPK), neuropeptide gamma (NP gamma), SP(4-11), SP(6-11), septide or [Sar9]SP sulphone. 5. In the absence or presence of SR 48,968, RP 67,580 antagonized in a competitive manner the response to septide, [Sar9]SP sulphone, SP(4-11) and SP(6-11): pKB values obtained in the absence and presence of SR 48,968 were not significantly different for any of these four agonists.6. RP 67,580 antagonized the response to SP and NKA both in the absence and presence of SR 48,968.In both cases, the slopes of the Schild plots were significantly different from unity. Mean dose-ratios produced by RP 67,580 in the presence of SR 48,968 were larger than those measured without NK2receptor blockade for both SP and NKA.7. RP 67,580 (3 MicroM) did not antagonize the response to NKB in the absence of SR 48,968. In the presence of SR 48,968, RP 67,580 acted as a competitive antagonist of NKB-induced contractions with apKB value (7.63) not significantly different from that measured towards septide. In the present of SR48,968, RP 67,580, GR 82,334 and (+/-)-CP 96,345 antagonized the response to NKB with a rank order of potency identical to that measured towards septide or [Sar9]SP sulphone.8. In the absence of SR 48,968, RP 67,580 (3 MicroM) produced a small shift of the concentration-response curve to neuropeptide K and was ineffective toward neuropeptide T. In the presence of SR 48,968 a clear shift of the curve to both agonists was observed.9. These findings are compatible with the idea that a septide-sensitive tachykinin receptor may exist in the rat urinary bladder. The septide-sensitive receptor is recognized by NK1 receptor antagonists with higher affinity than the 'classical' NK1 receptor recognized by [Sar9]SP sulphone. Our data suggest that NKB, after NK2 receptor blockade, is a more suitable ligand than SP for activation of the 'septidesensitive'receptor. While the final proof for the existence of possible NK1 receptor subtypes must await confirmation at the molecular level, the present findings provide strong pharmacological evidence that either NK, receptor subtypes or a novel type of tachykinin receptor exist in the rat urinary bladder.

The striatum is the main basal ganglia input nucleus, receiving extensive glutamatergic inputs from cortex and thalamus. Medium spiny striatal projection neurons (MSNs) are GABAergic, and their axon collaterals synapse on other MSNs. Approximately 50% of MSNs corelease substance P (SP), but how this neurotransmitter controls MSN activity is poorly understood. We used whole-cell recordings to investigate how SP affects MSNs and their glutamatergic inputs. SP elicited slow depolarizations in 47/90 MSNs, which persisted in the presence of tetrodotoxin (TTX). SP responses were mimicked by the NK1 receptor agonist [Sar9,Met(O(2))11]-substance P (SSP), and fully blocked by the NK1 receptor antagonists L-732,138, or extracellular zinc. When intracellular chloride was altered, the polarity of SP responses depended on the sign of the chloride driving force. In voltage-clamp, SP-induced currents reversed around -68 mV and displayed marked inward rectification. These data indicate that SP increased a ClC-2-type chloride conductance in MSNs, acting through NK1 receptors. SP also strongly increased glutamatergic responses in 49/89 MSNs. Facilitation of glutamatergic responses (which was observed both in MSNs directly affected by SP and in non-affected ones) was reduced by application of L-732,138, and fully blocked by coapplication of L-732,138 and SB222200 (an NK3 receptor antagonists), showing that both NK1 and NK3 receptors were involved. SP-induced facilitation of glutamatergic responses was accompanied by a marked decrease in paired-pulse ratio, indicating a presynaptic mechanism of action. These data provide an electrophysiological correlate for the anatomically known connections between SP-positive MSN terminals and the dendrites and somata of other MSNs.

Utilizing a human NK1 receptor antagonist (RPR 100893), the present in vivo study was designed to test the hypothesis that endogenous substance P (SP) modulates the action of 17beta-estradiol in inducing luteinizing hormone (LH) and follicle stimulating hormone (FSH) surges in ovariectomized cynomolgus monkey. Plasma concentrations of LH and FSH as well as NK1 receptor antagonist and SP were measured during the development of the negative and positive feedback phases which follow a single administration of estradiol benzoate (50 microg/kg) to long-term ovariectomized monkeys. Daily administration by gastric intubation of 1 mg/kg or 10 mg/kg of the NK1 receptor antagonist (RPR 100893) leads to detectable levels of the antagonist in the blood of treated animals for at least 6 hr after its administration. These levels are in agreement with the experimentally determined IC50 value of the antagonist. The most striking finding of this study is that LH and FSH releases are enhanced during the descending arm of the estradiol benzoate-induced LH and FSH surges, which suggests that endogenous SP normally has an inhibitory role during this time. The enhancement of LH release is approximately 50%, regardless of the amount of the NK1 antagonist used. However, the enhanced FSH release is more important. Furthermore, blockade of the NK1 receptor with the smaller dose of the antagonist leads to a small, but significant, increase in plasma levels of SP, indicating that blockade of SP receptors leads to an increased release of SP. Collectively, these results further substantiate the link which exists between the ovarian steroid 17beta-estradiol and SP systems. Also, for the first time, these results demonstrate an inhibitory involvement of the human NK1 receptor in the 17beta-estradiol-induced pseudo-ovulatory gonadotropin surges in the ovariectomized monkey.

1. Sensory nerves supplying the mammalian uterus have been shown to contain substance P (SP) and neurokinin (NK)A. This review presents some of the advances that have led to a greater understanding of the effects of tachykinins on uterine smooth muscle. 2. The cell-surface peptidase neprilysin (EC.3 24.11, endopeptidase 24.11, enkephalinase, CALLA, CD10) has been shown to play a major role in regulating the actions of tachykinins on both rat and human myometrium. Because this peptidase is known to be regulated by steroids and pregnancy, its effects may be of physiological relevance. 3. Tachykinins produce contractions of isolated myometrial preparations from non-pregnant rats and mice. The NK2 receptor mediates these effects in rat uterus, while the NK1 receptor may mediate these effects in the mouse uterus. 4. The effects of tachykinins have been examined on myometrial preparations obtained at Caesarean section from near-term pregnant women. In the presence of the peptidase inhibitors (thiorphan, captopril and bestatin), the mammalian tachykinins SP, NKA and NKB produced concentration-dependent uterine contractions. 5. The order of agonist potency NKA > SP = NKB suggested that NK2 receptors mediate uterine contractions in the human. This was confirmed using the stable analogues [Sar9,Met(O2)11]SP, [Lys5MeLeu9Nle10]NKA(4-10) and [N-MePhe7]NKB, which are NK1, NK2 and NK3 receptor selective, respectively. Only [Lys5MeLeu9Nle10]NKA(4-10) produced concentration-related contractions of human uterine smooth muscle. 6. The experimental findings described in the present review, taken together with results published previously in the literature, indicate that tachykinin peptides may play a physiological or pathophysiological role in regulating uterine smooth muscle activity. However, more extensive research will be required to confirm such a role for these peptides.

Role of NK-1 neurotransmission in opioid-induced hyperalgesia

1. The cardiovascular and behavioural effects elicited by the intracerebroventricular (i.c.v.) administration of neuropeptide gamma (NP gamma) in the conscious rat were assessed before and 5 min after i.c.v. pretreatment with antagonists selective for NK1 (RP 67,580), NK2 (SR 48,968) and NK3 (R 820) receptors. In addition, the central effects of NP gamma before and after desensitization of the NK1 and NK2 receptors with high doses of substance P (SP) and neurokinin A (NKA) were compared. 2. Intracerebroventricular injection of NP gamma (10-780 pmol) evoked dose- and time-dependent increases in mean arterial blood pressure (MAP), heart rate (HR), face washing, head scratching, grooming and wet-dog shake behaviours. Similar injection of vehicle or 1 pmol NP gamma had no significant effect on those parameters. 3. The cardiovascular and behavioural responses elicited by NP gamma (25 pmol) were significantly and dose-dependently reduced by pretreatment with 650 pmol and 6.5 nmol of SR 48,968. No inhibition of NP gamma responses was observed when 6.5 nmol of RP 67,580 was used in a similar study. Moreover, the prior co-administration of SR 48,968 (6.5 nmol) and RP 67,580 (6.5 nmol) with or without R 820 (6.5 nmol) did not reduce further the central effects of NP gamma and significant residual responses (30-50%) remained. 4. No tachyphylaxis to NP gamma-induced cardiovascular and behavioural changes was observed when two consecutive injections of 25 pmol NP gamma were given 24 h apart. 5. Simultaneous NK1 and NK2 receptor desensitization reduced significantly central effects mediated by 25 pmol NP gamma. However, significant residual responses persisted as seen after pretreatment with SR 48,968. 6. The results suggest that the central effects of NP gamma are mediated partly by NK2 receptors and by another putative tachykinin receptor subtype (NP gamma receptor?) that appears to be different from NK1 and NK3 receptors.

1. In the presence of atropine (1 microM), guanethidine (3 microM), indomethacin (3 microM), apamin (0.1 microM) and L-nitroarginine (L-NOARG, 30 microM), electrical field simulation (EFS) produced a nonadrenergic, noncholinergic (NANC) excitatory junctional potential (e.j.p.), action potentials and contraction of the circular muscle of the guinea-pig proximal duodenum, recorded by the single sucrose gap technique. 2. The selective tachykinin (TK) NK1 receptor antagonist, GR 82,334 (30 nM-3 microM) produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. and contraction. Similarly, the selective NK2 receptor antagonists, MEN 10,627 (30 nM-3 microM) and GR 94,800 (100 nM-10 microM), both produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. and contraction. GR 82,334 inhibited the electrical and mechanical NANC responses to EFS in an almost parallel manner, while MEN 10,627 and GR 94,800 were more effective in inhibiting the mechanical than the electrical response to EFS. 3. Activation of the NK1 or NK2 receptor by the selective agonists, [Sar9]substance P (SP) sulphone and [beta Ala8]neurokinin A (NKA) (4-10), respectively (0.3 microM each), produced depolarization, action potentials and contractions. GR 82,334 selectively inhibited the responses to [Sar9]SP sulphone, without affecting the responses to [beta Ala8]NKA (4-10). MEN 10,627 and GR 94,800 inhibited or abolished the responses to [beta Ala8]NKA (4-10), without affecting the responses to [Sar9]SP sulphone. 4. Nifedipine (1 microM) abolished the action potentials and contraction produced either by EFS or by the TK receptor agonists [Sar9]SP sulphone or [beta Ala8]NKA (4-10). 5. In the presence of nifedipine, the NANC e.j.p. produced by EFS was biphasic: in the majority of strips tested (21 out of 29) an early fast phase of depolarization was followed by a second slow component. The combined administration of GR 82,334 and GR 94,800 (3 microM each) reduced both components, the slow phase being inhibited to a greater extent than the fast phase. 6. The P2 purinoreceptor antagonist, suramin (100 microM) reduced the fast phase of the e.j.p. produced by EFS in the presence of nifedipine, without affecting the slow phase. The combined administration of suramin, GR 82,334 and GR 94,800 produced a nearly complete blockade of the e.j.p. produced by EFS in the presence of nifedipine. 7. When tested in the absence of apamin and L-NOARG, EFS induced a NANC inhibitory junction potential (i.j.p.) followed by an e.j.p., and the selective P2Y receptor agonist, adenosine-5'-O-(2-thiodiphosphate) (ADP beta S, 10 microM), produced membrane hyperpolarization. After addition of apamin and L-NOARG, the ij.p. was blocked, and EFS produced a pure NANC e.j.p.; ADPPS produced depolarization, action potentials and contraction.8. Suramin (100 microM) blocked the depolarization, action potentials and contractions produced by ADP beta S in the presence of apamin and L-NOARG, without affecting the responses produced by the NK1receptor agonist, [Sar9}SP sulphone.9. We conclude that NK1 and NK2 receptors cooperate in producing NANC excitation and contraction of the circular muscle in the guinea-pig proximal duodenum. Activation of either TK receptor produces membrane depolarization and both receptors contribute to generate action potentials which are essential for producing muscle contraction, via nifedipine-sensitive calcium channels. It appears that endogenous ATP chiefly acts as an inhibitory transmitter but, after blockade of NANC inhibitory mechanism(s),ATP may act as a fast signalling excitatory transmitter.

顽固性癌痛的治疗是一公认的世界性难题.早在1986年,世界卫生组织曾推荐一个由阿司匹林、可卡因到吗啡的三阶梯方案[1].但即使给足够量的镇痛药和系统的正规治疗,仍有相当一部份顽固性癌痛患者不能有效缓解疼痛,或者不能耐受长期大剂量强效镇痛药所带来的副作用,而需寻求所谓第四阶梯治疗,即外科手术的治疗.现结合文献将常用外科治疗方法综述如下。

Administration of intraspinal morphine sulfate for the treatment of intractable cancer pain : Neurosurgery, 18 (1986) 740–747

Disconnecting Pain: Neurosurgical Interventions for the Treatment of Intractable Cancer Pain (FR441C)

Three Cases of Patients Referred to a Specialist Pain Unit for Treatment of Intractable Cancer Pain

Successful Use of Ketamine Infusion in the Treatment of Intractable Cancer Pain in an Outpatient

Evidence for the involvement of the Substance P (SP)/NK1 receptor system in the development and progression of cancer strongly supports its potential as a therapeutic target in malignancies. Novel strategies for approaching cancer treatment are urgently required particularly with regard to tumours of the central nervous system (CNS), which are notoriously difficult to effectively treat and associated with extremely poor prognosis for many patients. This is due, in part, to the presence of the highly specialised blood-brain barrier, which is known to restrict common treatments such as chemotherapy and hinder early tumour diagnosis. Additionally, tumours of the CNS are difficult to surgically resect completely, often contributing to the resurgence of the disease many years later. Interestingly, despite the presence of the blood-brain barrier, circulating tumour cells are able to gain entry to the brain and form secondary brain tumours; however, the underlying mechanisms of this process remain unclear. Tachykinins, in particular Substance P, have been implicated in early blood-brain barrier disruption via neurogenic inflammation in a number of other CNS pathologies. Recent evidence also suggests that Substance P may play a central role in the development of CNS tumours. It has been well established that a number of tumour cells express Substance P, NK1 receptors and mRNA for the tachykinin NK1 receptor. This increase in the Substance P/NK1 receptor system is known to induce proliferation and migration of tumour cells as well as stimulate angiogenesis, thus contributing to tumour progression. Accordingly, the NK1 receptor antagonist presents a novel target for anti-cancer therapy for which a number of patents have been filed. This review will examine the role of Substance P in the development of CNS tumours and its potential application as an anti-cancer agent.