How complete and accurate are cancer registrations notified by the National Health Service Central Register for England and Wales?

STUDY OBJECTIVE: To assess the completeness and accuracy of notification of cancers by the National Health Service Central Register (NHSCR) for England and Wales. DESIGN: Comparison of 720 cancer registrations ascertained from NHSCR up to May 1999 with those ascertained for the same cohort from six other sources and a pathology review of the NHSCR cancer registrations. PARTICIPANTS: People born in Cumbria, north west England, 1950-89, and diagnosed with cancer throughout the UK, 1971-1989. MAIN RESULTS: Cancer diagnoses notified by NHSCR differed substantially from those determined by this pathology review for 47 of the 688 notified cases reviewed (7%; 95% CI 5%, 9%). Over one third of these discrepancies were attributable to failures in data capture or coding by the cancer registration system and almost half to changes in diagnosis; 26 of the 47 discrepant cases were reclassified as non-malignant and 21 as malignancies but with a substantially different diagnosis. The 694 confirmed malignancies represented 94% (95%CI 92%, 95%) of the 740 cancers ascertained from all sources. CONCLUSIONS: It is estimated that the cancer registration system missed at least 10% (95%CI 6%, 15%) of all incident cases of malignant disease. Without additional ascertainment from multiple sources and diagnostic review, it would be incautious to use NHSCR cancer registrations as the sole basis of an epidemiological study.

Verruciform xanthoma of the nose.

We report a case of verruciform xanthoma of the nasal skin. The case is unique because the lesion both bled and has shown evidence of multicentricity.

Effect of pre-emptive NMDA antagonist treatment on long-term Fos expression and hyperalgesia in a model of chronic neuropathic pain.

The unilateral sciatic nerve chronic constriction injury (CCI) model of Bennett and Xie [G.J. Bennett, Y.-K. Xie, A peripheral neuropathy in rat that produces disorders of pain sensation like those seen in man, Pain, 33 (1988) 87-108] shows features of a neuropathic pain state. We examined mechanical hyperalgesia and Fos protein staining in the lumbar spinal cord 1, 7, 14 and 28 days after unilateral CCI to the sciatic nerve or sham operation. In addition, we examined the effect of the NMDA antagonist MK-801 (0.3 mg/kg s.c. administered 30 min prior to and 6 h following operation) on Fos expression and hyperalgesia at 28 days. CCI animals were hyperalgesic compared to the sham operated animals at 14 and 28 days post injury. MK-801 reduced hyperalgesia by 68% in CCI animals on day 28 (p=0.0001). In the spinal cord, Fos positive cells were present bilaterally in deeper laminae in both sham and CCI animals at all time points examined. Relatively few Fos positive cells were present in laminae 1-2 at any time point examined. At days 1 and 7, there were increased numbers of Fos positive cells ipsilaterally in the deeper laminae of the spinal cord in CCI animals compared to sham animals, but by 14 and 28 days Fos counts were similar in sham and CCI despite the obvious behavioural differences between the two groups. Fos counts ipsilateral to the injury in laminae 3-10 correlated with hyperalgesia scores in the CCI but not sham animals. Analysis at the 28-day time point showed that MK-801 differentially affected Fos expression: MK-801 significantly reduced the Fos count bilaterally in laminae 3-10 in the CCI but not in the sham group animals. These results indicate that Fos expression is initiated by different peripheral and central mechanisms following nerve injury or sham operation.

Effect of post-injury NMDA antagonist treatment on long-term Fos expression and hyperalgesia in a model of chronic neuropathic pain.

Chronic constriction injury (CCI) of the sciatic nerve results in persistent mechanical hyperalgesia together with Fos protein expression in the lumbar spinal cord. We have examined the relationship between mechanical hyperalgesia and Fos expression within the lumbar spinal cord on days 14, 35 and 55 after either CCI or sham operation. To determine the role of NMDA receptor mechanisms in the maintenance of hyperalgesia and Fos expression, the NMDA antagonist MK-801 (0.3 mg kg-1 s.c.) was administered daily on days 28 to 34 after operation. CCI animals developed unilateral hind limb hyperalgesia that persisted unchanged from days 14 to 55 of the study. MK-801 treatment reduced hyperalgesia by 57% (p=0.02) on day 35 in CCI animals but did influence hyperalgesia at day 55. In the spinal cord, Fos positive cells were present bilaterally throughout laminae 3-10 at all time points examined in both CCI and sham group animals. Fos counts ipsilateral to the side of injury in laminae 3-10 correlated significantly with hyperalgesia scores in the CCI but not sham animals. MK-801 treatment resulted in a suppression of Fos expression in ipsilateral laminae 3-4 (p=0.0017) and laminae 5-10 (p=0.0026) of CCI animals on day 35. Fos expression in sham group animals was not inhibited by MK-801 treatment at day 35. These results indicate that Fos expression is maintained by differing mechanisms following nerve injury or sham operation. The functional consequences of Fos expression following nerve injury and sham operation are discussed.

Behavioural and electrophysiological evidence supporting a role for group I metabotropic glutamate receptors in the mediation of nociceptive inputs to the rat spinal cord.

A combined study of behavioural and electrophysiological tests was carried out in order to assess the role of metabotropic glutamate receptors (mGluRs) in mediating sensory inputs to the spinal cord of the rat. In the behavioural study the responses of conscious animals, with or without carrageenan-induced inflammation, to noxious mechanical and thermal stimuli were observed both before and after the intrathecal administration of mGluR antagonists L(+)-2-amino-3-phosphonopropionic acid (L-AP3) and (S)-4-carboxy-3-hydroxyphenylglycine (CHPG). It was found that the mGluR antagonist (S)-CHPG was capable of increasing both mechanical threshold and thermal latency in both groups of animals, and L-AP3 did so in those with inflammation induced in their hindpaw. Following this study, the responses of single lamina III-V dorsal horn neurons to an innocuous A beta fibre brush stimulus and a noxious C fibre (mustard oil) stimulus were extracellularly recorded and the effect of ionophoretically applied drugs was examined. Cyclothiazide (CTZ), a selective antagonist at mGluR1, markedly reduced the activity evoked by mustard oil, but not that elicited by brushing of the receptive field. Activity induced in dorsal horn neurons by ionophoresing various mGluR subgroup agonists was examined. CTZ successfully inhibited the activity evoked by group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG). In comparison to the neurons which responded to the ionophoresis of DHPG, less were activated by the selective mGluR5 agonist trans-azetidine dicarboxylic acid (t-ADA). Together these results indicate that group I mGlu receptors, in particular mGluR1, play a crucial role in mediating nociception, particularly following a sustained noxious input.

Neuropeptide changes persist in spinal cord despite resolving hyperalgesia in a rat model of mononeuropathy.

We have previously described the changes in spinal cord neuropeptides in the unilateral sciatic chronic constriction injury (CCI) model of Bennett and Xie [Pain, 33 (1988) 87-108] at 28 days, a time of maximum mechanical hyperalgesia. In this study we examine the same model 100-120 days post injury by which time resolution of the hyperalgesia and peripheral nerve injury has occurred according to previous studies. Rats underwent either CCI of the sciatic nerve (n = 12) or else sham operation (n = 8) which involved exposure but no ligation of the nerve. Mechanical hyperalgesia was assessed with a Ugo-Basile analgesymeter and immunohistochemistry performed on the spinal cord sections of the animals and quantified using a confocal microscope. At this late time point CCI rats were no longer significantly mechanically hyperalgesic compared to the sham animals (P > or = 0.09). However, examination of the lumbar spinal cord revealed the following changes. (i) The neuropeptides substance P (SP) (P < 0.0001) and galanin (P < 0.003) both showed decreases of about 30% ipsilaterally in immunoreactivity in laminae 1 and 2 of the dorsal horn compared to the sham operated animals. (ii) Calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY) in laminae 1 and 2 showed no significant changes compared to sham animals. (iii) NPY levels in laminae 3 and 4 of the spinal cord showed a 15% increase in immunoreactivity compared to sham animals (P = 0.008). These results indicate that changes in neuronal markers in the spinal cord can persist after apparent resolution of a peripheral nerve injury. We suggest that these changes may form a substrate for subsequent development of abnormal pain states.

The pharmacology of GR203040, a novel, potent and selective non-peptide tachykinin NK1 receptor antagonist.

1. The in vitro and in vivo pharmacology of GR203040 ((2S, 3S)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), a novel, highly potent and selective non-peptide tachykinin NK1 receptor antagonist, was investigated in the present study. 2. GR203040 potently inhibited [3H]-substance P binding to human NK1 receptors expressed in Chinese hamster ovary (CHO) and U373 MG astrocytoma cells, and NK1 receptors in ferret and gerbil cortex (pKi values of 10.3, 10.5, 10.1 and 10.1 respectively). GR203040 had lower affinity at rat NK1 receptors (pKi = 8.6) and little affinity for human NK2 receptors (pKi < 5.0) in CHO cells and NK3 receptors in guinea-pig cortex (pKi < 6.0). With the exception of the histamine H1 receptor (pIC50 = 7.5). GR203040 had little affinity (pIC50 < 6.0) at all non-NK1 receptors and ion channels examined. Furthermore, GR203040 produced only weak inhibition of Na+ currents in SH-SY5Y neuroblastoma and superior cervical ganglion cells (pIC50 values < 4.0). GR203040 produced only weak antagonism of Ca(2+)-evoked contractions of rat isolated portal vein (pKn = 4.1). The enantiomer of GR203040, GR205608 (2R, 3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), had 10,000 fold lower affinity at the human NK1 receptor expressed in CHO cells (pKi = 6.3). 3. In gerbil ex vivo binding experiments, GR203040 produced a dose-dependent inhibition of the binding of [3H]-substance P to cerebral cortical membranes (ED50 = 15 micrograms kg-1 s.c. and 0.42 mg kg-1 p.o.). At 10 micrograms kg-1 s.c., the inhibition of [3H]-substance P binding was maintained for > 6 h. In the rat, GR203040 was less potent (ED50 = 15.4 mg kg-1 s.c.) probably reflecting, at least in part, its lower affinity at the rat NK1 receptor. 4. In guinea-pig isolated ileum and dog isolated middle cerebral and basilar arteries, GR203040 produced a rightward displacement of the concentration-effect curves to substance P methyl ester (SPOMe) with suppression of the maximum agonist response (apparent pKB values of 11.9, 11.2 and 11.1 respectively). 5. In anaesthetized rabbits, GR203040 antagonized reductions in carotid arterial vascular resistance evoked by SPOMe, injected via the lingual artery (DR10 (i.e. the dose producing a dose-ratio of 10) = 1.1 micrograms kg-1, i.v.). At a dose 20 fold greater than its DR10 value (i.e. 22 micrograms kg-1, i.v.), significant antagonism was evident more than 2 h after GR203040 administration. 6. In anaesthetized rats, GR203040 (3 and 10 mg kg-1, i.v.) produced a dose-dependent inhibition of plasma protein extravasation in dura mater, conjunctiva, eyelid and lip in response to electrical stimulation of the trigeminal ganglion. 7. It is concluded that GR203040 is one of the most potent and selective NK1 receptor antagonists yet described, and as such, has considerable potential as a pharmacological tool to characterize the physiological and pathological roles of substance P and NK1 receptors. GR203040 may also have potential as a novel therapeutic agent for the treatment of conditions such as migraine, emesis and pain.

Changes in neuronal markers in a mononeuropathic rat model relationship between neuropeptide Y, pre-emptive drug treatment and long-term mechanical hyperalgesia.

Using the chronic constriction model (CCI) of Bennett and Xie (1988), changes in the lumbar spinal cord in neuropeptides and lectin IB4 were examined at 28 days post-nerve constriction and were compared with the degree of mechanical hyperalgesia. Animals following nerve ligation were significantly more hyperalgesic than sham-operated animals (P < 0.0001). Lectin IB4, a marker of primary afferent C fibres, showed a qualitative decrease in staining intensity in laminae 1-2 with ligation compared with both the unoperated contralateral side and with sham animals. Using fluorescent immunohistochemistry to quantify changes in neuropeptides in the dorsal horn we found that substance P showed significant decreases with ligation compared to sham operation (P < 0.002). CGRP and galanin showed no significant changes in laminae 1-2 compared to sham-operated animals. Neuropeptide Y (NPY) showed no significant changes in intensity in laminae 1-2; however, in laminae 3-4 there was a significant increase with nerve ligation compared to sham (P < 0.005). We examined how pre-emptive drug treatment affected these neuronal markers at 28 days. We used (1) clonidine, an alpha 2-adrenoreceptor agonist (1 mg/kg, i.p.), (2) morphine, a mu-opioid agonist (5 mg/kg, i.p.) or (3) MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist (0.3 mg/kg, s.c.) administered 30 min prior and 6 h following nerve ligation or sham-operation. Hyperalgesia in the ligated group at 28 days was suppressed by treatment with pre-emptive clonidine (P = 0.003) or MK-801 (P = 0.003) but not morphine. With the exception of NPY there was no effect of pre-emptive drug treatment on any neuronal marker examined. Pre-emptive MK-801 reduced the magnitude of the increase in NPY in laminae 3-4 in the ligated group (P < 0.005) and clonidine showed a similar trend but this did not reach significance. Morphine had no effect on NPY staining. There was a significant correlation between the increase in NPY staining in laminae 3-4 and the degree of hyperalgesia (r = 0.6, P < 0.001). These results suggest that the increased NPY expression in laminae 3-4 of the spinal cord (the territory of the myelinated sensory input) may be crucial to the development of hyperalgesia in this model.

Longstanding proliferation of CD3 negative large granular lymphocytes preceding the development of high grade non-Hodgkin's lymphoma.

A patient with a persistent CD3 negative large granular lymphocyte (LGL) proliferation with immunophenotypic and functional characteristics of natural killer cells is described. The LGL proliferation persisted and six years after diagnosis the patient developed a high grade B cell non-Hodgkin's lymphoma. Molecular studies demonstrated clonal B cell populations in the peripheral blood, distinct from that identified in the lymphoma, both at presentation with non-Hodgkin's lymphoma and at complete remission following combination chemotherapy. It is postulated that T cell dysregulation associated with the CD3 negative LGL proliferation may have led to B cell dysfunction and loss of normal B cell control, with the subsequent development of a clonal B cell lymphoproliferative disorder.

Endogenous modulation of excitatory amino acid responsiveness by tachykinin NK1 and NK2 receptors in the rat spinal cord.

1. The effects of selective tachykinin (neurokinin, NK) NK1 and NK2 receptor antagonists have been examined on spinal neurones in alpha-chloralose anaesthetized, spinalized rats. They were tested for effects on responses both to excitatory amino acids (EAA) and to noxious heat stimuli. They were also tested for their ability to reverse the actions of selective NK agonists. 2. The NK1-selective antagonists GR82334 (peptide) and CP-99,994 (non-peptide), when applied by microiontophoresis, both reduced responses to kainate > AMPA > NMDA. Intravenous CP-99,994 (3 mg kg-1) also reduced responses to kainate but had inconsistent effects on nociceptive responses. 3. GR82334, applied microiontophoretically, reduced the enhancement by the selective NK1 agonist, GR73632 of both responses to EAAs and background activity. Systemic CP-99,994 (< or = 10 mg kg-1) failed to reverse the effects of GR73632. 4. The selective peptide NK2 antagonist, GR103537, had no consistent effects on responses to EAAs when applied by iontophoresis. In contrast, the non-peptide NK2 antagonist, GR159897, administered systemically (0.5-2 mg kg-1, i.v.) enhanced responses to kainate (but not NMDA); responses to noxious heat were enhanced only weakly. 5. Iontophoretically-administered GR103537 attenuated the effects of the NK2 agonist GR64349, which selectively reduced responses to kainate compared to those to NMDA. Systemically administered GR159897 (< or = 2 mg kg-1, i.v.) caused little antagonism of the effects of GR64349. 6. The data indicate that under these conditions the non-peptide antagonists are not reliable at reversing the actions of selective NK agonists. 7. These results suggest that there is a tonic release of endogenous tachykinins that can modulate glutamatergic neurotransmission in the spinal cord. They provide further support for the hypothesis that release of endogenous NKs acting on NK1 and NK2 receptors can promote NMDA receptor mediated glutamatergic transmission.

Peri-administration of clonidine or MK801 delays but does not prevent the development of mechanical hyperalgesia in a model of mononeuropathy in the rat.

Following loose ligation of the sciatic nerve, rats develop a persistent hyperalgesia which mimics some of the features of traumatic neuropathy seen in man. Previously, we have shown that administration of MK801 or clonidine prior to and 30 min following loose ligation of the sciatic nerve prevented the development of hyperalgesia up to 30 days following surgery. In the current study, we have extended our observation and examined the effect of administration of clonidine (1 mg/kg, s.c.) or MK801 (0.3 mg/kg, s.c.) 30 min prior to and 6 h following loose ligation of the sciatic nerve on the development of hyperalgesia assessed at 9 time points between 16 and 150 days after loose ligation. We have found that compared with saline treatment, the degree of hyperalgesia apparent in animals receiving MK801 was significantly reduced when tested 16, 28, or 42 days after surgery. No significant difference between the 2 treatment groups was detected at any other time points during the study. Similarly, when compared with saline treated controls, the degree of hyperalgesia measured in animals following peri-administration of clonidine was significantly less when measured 16 and 28 days after surgery, but did not differ significantly at any of the time points tested between 42 and 150 days following surgery. Our results indicate that peri-administration of MK801 or clonidine significantly delay, but do not prevent, the onset of neuropathic hyperalgesia.

Inhibition of constitutive and inducible cyclooxygenase activity in human platelets and mononuclear cells by NSAIDs and Cox 2 inhibitors.

A range of NSAIDs and reported Cox 2 selective compounds were tested in human freshly isolated platelets and LPS-stimulated mononuclear cells to determine their potency and selectivity as inhibitors of constitutive (presumably Cox 1) and inducible (presumably Cox 2) cyclooxygenase respectively. All compounds tested were either equipotent at inhibiting constitutive and inducible cyclooxygenase or were selective for the inducible form. The most selective compound was Dup697 and the least selective, ketoprofen. Several compounds only produced a partial inhibition of constitutive cyclooxygenase as the maximum inhibitor concentration achievable in the assay was limited to 1 mM. With the exception of paracetamol, all compounds were able to produce full inhibition curves against the inducible form. Potency estimates against constitutive Cox compare closely with published data but most compounds were consistently more potent against the inducible isoform than in published data for human cloned, microsomal Cox 2. These data suggest that human mononuclear cells are either exquisitely sensitive to some NSAIDs or they may contain another Cox isoform as yet indistinguishable from Cox 2.

Increased sensitivity to the antinociceptive activity of (+/-)-baclofen in an animal model of chronic neuropathic, but not chronic inflammatory hyperalgesia.

Modulation of sensory afferent inputs to the spinal cord by GABA appears to be an important physiological mechanism and may provide an antinociceptive control system. In the present study we have evaluated the antinociceptive activity of the GABAB receptor agonist, (+/-)-baclofen, in rats with unilateral chronic inflammatory or neuropathic hyperalgesia. (+/-)-Baclofen was antinociceptive in untreated control animals and both animal models. In the neuropathic model the sensitivity to (+/-)-baclofen was significantly increased by 3-fold in the ipsilateral limb. By contrast, in animals with chronic inflammation no difference in sensitivity between ipsilateral and contralateral limbs to (+/-)-baclofen was observed. Receptor autoradiographic analysis in spinal cord sections revealed no increase in the density of GABAB receptor binding sites and no change in receptor affinity in the neuropathic model.

4-[(Alkylamino)methyl]furo[3,2-c]pyridines: a new series of selective kappa-receptor agonists.

The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2-c] pyridines (16-23, 26, 27) and their activities as kappa-opioid receptor agonists are described. kappa-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (kappa-specific tissue), the 3-pyrrolidinol analogue 17 (IC50 = 2.7 nM) was found to be approximately 5-fold more potent than the corresponding pyrrolidine analogue 16 (IC50 = 15 nM). In the rat and hamster vasa deferentia (mu-specific and delta-specific tissues, respectively), 17 showed only weak antagonist activity (pKB > 5.5), underlining its selectivity for the kappa-opioid receptor. The major activity for 17 is resident in the 4S,3'S-isomer 26 (rabbit vas deferens IC50 = 1.1 nM). Compound 26 displays excellent antinociceptive activity, as determined in the mouse acetylcholine-induced abdominal constriction test (ED50 = 0.001 mg/kg, sc).

Pre treatment with MK-801, a non-competitive NMDA antagonist, prevents development of mechanical hyperalgesia in a rat model of chronic neuropathy, but not in a model of chronic inflammation.

In the rat, loose ligation of the sciatic nerve results in behavioural signs of hyperalgesia reminiscent of neuropathy in man. A further rat model, of chronic inflammatory hyperalgesia, is produced by intraplantar administration of Freund's complete adjuvant (FCA). We report here that preemptive administration of a non-competitive antagonist of the glutamate N-methyl-D-aspartate (NMDA) receptor, MK-801 (0.3 mg kg-1, s.c.) 30 min prior to and twice daily for a further 8 days following loose ligation of the sciatic nerve, blocks the development of mechanical hyperalgesia measured 27 days later. In contrast, MK-801 administration using the same dosing regimen did not significantly inhibit the hyperalgesia apparent 15 days following i.pl. administration of FCA. Our results suggest that the mechanisms responsible for the development of mechanical hyperalgesia associated with chronic nerve injury and chronic inflammation differ.

Pre-emptive administration of clonidine prevents development of hyperalgesia to mechanical stimuli in a model of mononeuropathy in the rat.

Traumatic nerve injury in man can often result in the development of neuropathy. An animal model of neuropathic hyperalgesia is produced by loose ligation of the sciatic nerve in the rat. We have examined the effect of pre-emptive treatment with a number of drugs on the development of hyperalgesia in this model. Animals received clonidine (1 mg.kg-1, s.c.), morphine (5 mg.kg-1, s.c.), (+/-)-baclofen (40 mg.kg-1, s.c.), carbamazepine (50 mg.kg-1, s.c.) or vehicle (4 ml.kg-1, s.c.) 30 min prior to loose ligation or sham-operation. Morphine- and clonidine-treated animals were administered a second dose of drug 6h following surgery. Twenty-six or twenty-nine days following surgery, the ipsilateral (ipsi.) and contralateral (contra.) paw withdrawal thresholds were determined using an Algesymeter. In vehicle-treated animals the ipsilateral paw withdrawal threshold (118 +/- 7 g) was significantly lower (P < 0.0001, paired t-test) than the contralateral (195 +/- 7 g). In contrast, in animals pre-treated with clonidine no significant difference between ipsilateral (200 +/- 9 g) and contralateral (191 +/- 7 g) paw withdrawal thresholds was detected. Morphine pre-treatment was less effective in preventing development of hyperalgesia; however, whilst the ipsilateral (146 +/- 18 g) paw withdrawal threshold tended to be lower than the contralateral (183 +/- 8 g), this was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Glutathione-S-transferase pi expression in transitional cell carcinoma of the bladder.

Glutathione-S-transferase pi (GST pi) is a multifunctional protein that acts as an enzyme, involved in the detoxification of drugs and carcinogens. It has been implicated both in drug resistance and malignant transformation of epithelium. Using an indirect immunohistochemical technique, we have evaluated cytoplasmic and nuclear staining in normal urothelium, 23 superficial bladder tumours and 26 invasive tumours. All 26 invasive tumours had been treated with platinum-based chemotherapy. Cytoplasmic staining was seen in normal urothelium and all bladder tumours. Nuclear staining was seen in 1 superficial tumour and in 13 invasive tumours. There was no association between nuclear staining and response to chemotherapy. Nuclear staining was seen in 1 area of dysplasia and in 2 of 3 areas of carcinoma in situ. GST pi expression is not a predictor of response to chemotherapy. Increased intra-nuclear expression of GST pi may be associated with progression of transitional cell carcinoma of the bladder.

A potent new class of kappa-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines.

The synthesis of 4-substituted 1-(arylacetyl)-2-[(alkylamino)methyl]piperazines (10-22, 26, 27, and 30-33) and their activities as kappa-opioid receptor agonists are described. This includes a range of 4-acyl and 4-carboalkoxy derivatives with the latter series showing the greatest kappa-agonist activity. In particular, methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate (18) displays exceptional potency and selectivity. It showed the following activities in functional in vitro assays: rabbit vas deferens (kappa-specific tissue) IC50 = 0.041 nM, rat vas deferens (mu-specific tissue) IC50 > 10,000 nM, and hamster vas deferens (delta-specific tissue) IC50 > 10,000 nM. Compound 18 is also a highly potent antinociceptive agent, as determined in the mouse acetylcholine-induced abdominal constriction test: ED50 = 0.000 52 mg/kg, sc. The activity of 18 resides solely in its 3(R)-enantiomer. The kappa-agonist activity in both the 4-acyl and the 4-carbamate series is sensitive to the size of the 4-substituent. In addition, it would appear that an appreciable negative electrostatic potential in this region of the molecule is an important requirement for optimal potency.