Efficacy of accelerated hydrogen peroxide® disinfectant on foot-and-mouth disease virus, swine vesicular disease virus and Senecavirus A.

AIMS: In a laboratory, disinfectants used to inactivate pathogens on contaminated surfaces and to prevent spread of diseases often have adverse side effects on personnel and the environment. It is, therefore, essential to find safer, fast-acting and yet effective disinfectants. The objective of this study was to evaluate an accelerated hydrogen peroxide® (AHP® )-based disinfectant against high consequence foreign animal disease pathogens such as foot-and-mouth disease virus (FMDV) and swine vesicular disease virus (SVDV), as well as Senecavirus A (SVA), which causes similar lesions as FMDV and SVDV. METHODS AND RESULTS: We tested varying dilutions and contact times of AHP against FMDV, SVDV and SVA by the standard US EPA and modified methods. AHP was effective against all three viruses, albeit at a higher concentration and double the manufacturer recommended contact time when testing wet films of SVDV. CONCLUSIONS: AHP is an effective disinfectant against FMDV, SVDV and SVA. SIGNIFICANCE AND IMPACT OF THE STUDY: AHP-based disinfectant can, therefore, be used in high containment laboratories working with FMDV, SVDV and related pathogens.

The tumour hypoxia marker pimonidazole reflects a transcriptional programme associated with aggressive prostate cancer.

BACKGROUND: The hypoxia marker pimonidazole is a candidate biomarker of cancer aggressiveness. We investigated the transcriptional programme associated with pimonidazole staining in prostate cancer. METHODS: Index tumour biopsies were taken by image guidance from an investigation cohort of 52 patients, where 43 patients received pimonidazole before prostatectomy. Biopsy location within the index tumour was verified for 46 (88%) patients, who were included for gene expression profiling and immunohistochemistry. Two independent cohorts of 59 and 281 patients were used for validation. RESULTS: Expression of genes in proliferation, DNA repair and hypoxia response was a major part of the transcriptional programme associated with pimonidazole staining. A signature of 32 essential genes was constructed and showed positive correlation to Ki67 staining, confirming the increased proliferation in hypoxic tumours as suggested from the gene data. Positive correlations were also found to tumour stage and lymph node status, but not to blood prostate-specific antigen level, consistent with the findings for pimonidazole staining. The association with aggressiveness was confirmed in validation cohorts, where the signature correlated with Gleason score and had independent prognostic impact, respectively. CONCLUSIONS: Pimonidazole staining reflects an aggressive hypoxic phenotype of prostate cancer characterised by upregulation of proliferation, DNA repair and hypoxia response genes.

Two escalated followed by six standard BEACOPP in advanced-stage high-risk classical Hodgkin lymphoma: high cure rates but increased risk of aseptic osteonecrosis.

BACKGROUND: From 1999, Norwegian guidelines recommend two escalated (esc) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) followed by six standard (s) BEACOPP for patients with advanced-stage classical Hodgkin lymphoma (HL) with an international prognostic score (IPS) ≥ 4. We evaluated retrospectively the experience with this recommendation at the Norwegian Radium Hospital, also including all IPS 3 patients treated with the same regimen. PATIENTS AND METHODS: Forty-seven patients were treated between June 1999 and December 2008. IPS was 3 in 10 patients and ≥ 4 in 37. RESULTS: Thirty-five patients received eight cycles of BEACOPP, 12 patients received one to six cycles only, mainly due to toxicity. Sixty percent of patients had dose reductions. With median follow-up of survivors of 89 months, 5-year progression-free and overall survival are 84% [95% confidence interval (CI) 73% to 95%] and 91% (95% CI 82% to 100%), respectively. Toxicity was considerable with grade 3 or more infections/febrile neutropenia in 66% of patients, including one death and three cases of Pneumocystis jiroveci pneumonia. Of note, 10 patients (21%) experienced symptomatic aseptic osteonecrosis, of whom 3 have had hip replacement surgery after treatment. CONCLUSION: Two escBEACOPP plus six sBEACOPP is efficacious in advanced-stage high-risk HL. We document a high incidence of aseptic bone necrosis, possibly related to prednisolone.

MRI and neurological findings in patients with spinal metastases.

BACKGROUND: Magnetic resonance imaging (MRI) is the recommended primary investigation method for metastatic spinal cord compression (MSCC). Initiating treatment before the development of motor deficits is essential to preserve neurological function. However, the relationship between MRI-assessed grades of spinal metastatic disease and neurological status has not been widely investigated. PURPOSE: To analyze the association between neurological function and MRI-based assessment of the extent of spinal metastases using two different grading systems. MATERIAL AND METHODS: A total of 284 patients admitted to our institution for initial radiotherapy or surgery for symptomatic spinal metastases were included in the study. Motor and sensory deficits were categorized according to the Frankel classification system. Pre-treatment MRI evaluations of the entire spine were scored for the extent of spinal metastases, presence and severity of spinal cord compression, and nerve root compression. Two MRI-based scales were used to evaluate the degree of cord compression and spinal canal narrowing and relate these findings to neurological function. RESULTS: Of the patients included in the study, 28 were non-ambulatory, 49 were ambulatory with minor motor deficits, and 207 had normal motor function. Spinal cord compression was present in all patients with Frankel scores of B or C, 23 of 35 patients with a Frankel score of D (66%), and 48 of 152 patients with a Frankel score of E (32%). The percentage of patients with severe spinal canal narrowing increased with increasing Frankel grades. The grading according to the scales showed a significant association with the symptoms according to the Frankel scale (P < 0.001). CONCLUSION: In patients with neurological dysfunction, the presence and severity of impairment was associated with the epidural tumor burden. A significant number of patients had radiological spinal cord compression and normal motor function (occult MSCC).

Neoadjuvant chemotherapy in breast cancer-response evaluation and prediction of response to treatment using dynamic contrast-enhanced and diffusion-weighted MR imaging.

OBJECTIVE: To explore the predictive value of MRI parameters and tumour characteristics before neoadjuvant chemotherapy (NAC) and to compare changes in tumour size and tumour apparent diffusion coefficient (ADC) during treatment, between patients who achieved pathological complete response (pCR) and those who did not. METHODS: Approval by the Regional Ethics Committee and written informed consent were obtained. Thirty-one patients with invasive breast carcinoma scheduled for NAC were enrolled (mean age, 50.7; range, 37-72). Study design included MRI before treatment (Tp0), after four cycles of NAC (Tp1) and before surgery (Tp2). Data in pCR versus non-pCR groups were compared and cut-off values for pCR prediction were evaluated. RESULTS: Before NAC, HER2 overexpression was the single significant predictor of pCR (p = 0.006). At Tp1 ADC, tumour size and changes in tumour size were all significantly different in the pCR and non-pCR groups. Using 1.42 × 10(-3) mm(2)/s as the cut-off value for ADC, pCR was predicted with sensitivity and specificity of 88% and 80%, respectively. Using a cut-off value of 83% for tumour volume reduction, sensitivity and specificity for pCR were 91% and 80%. CONCLUSION: ADC, tumour size and tumour size reduction at Tp1 were strong independent predictors of pCR.

Extended total mesorectal excision in locally advanced rectal cancer (T4a) and the clinical role of MRI-evaluated neo-adjuvant downstaging.

OBJECTIVE: To compare the clinical ability of MRl taken before and after neo-adjuvant treatment in locally advanced rectal cancer (LARC) to predict the necessary extension of TME (ETME) and the possibility to achieve a R0 resection. METHOD: Prospective registration of 92 MRI evaluated T4a cancers undergoing elective surgery between 2002 and 2007 in a tertiary referral centre for multimodal treatment of rectal cancer. RESULTS: MRI identified patients in need of neo-adjuvant treatment and predicted T-downstaging in 10% and N-downstaging in 59%. Seventy-nine percent R0 resections, 18% R1 and 3% R2 were obtained after ETME in 95% of the patients and TME in the rest. Higher tumour regression grade (TRG) was achieved in higher ypT-stage (P < 0.01). Preoperative chemo radiotherapy resulted in that more patients obtained TRG1-3 compared to those receiving radiotherapy (79% vs. 57%, P = 0.02). The pelvic wall was the area of failure in 70% of the R1 resections. Tumour cells outside the mesorectal fascia scattered within fibrosis was found in 18 TRG2-3 among 33 ypT4 tumours (55%). CONCLUSION: MRl cannot discriminate tumour within fibrosis. Therefore, if a R0 resection is the goal, we advocate optimal surgery in accordance with the pre-treatment MRI. Post treatment MRI is a poor predictor of final histology and should not be relied upon to guide the extent of surgical resection. The study has initiated a new approach to histopathological classification of the removed specimen where we introduce a MRI assisted technique for investigating the areas at risk outside the mesorectal fascia in the specimen.

Foot-and-Mouth Disease in Red Deer - Experimental Infection and Test Methods Performance.

The aim of this study was to evaluate a number of foot-and-mouth disease (FMD) test methods for use in red deer. Ten animals were intranasally inoculated with the FMD virus (FMDV) O UKG 11/2001, monitored for clinical signs, and samples taken regularly (blood, serum, oral swabs, nasal swabs, probang samples and lesion swabs, if present) over a 4-week period. Only one animal, deer 1103, developed clinical signs (lesions under the tongue and at the coronary band of the right hind hoof). It tested positive by 3D and IRES real-time reverse transcription polymerase chain reaction (rRT-PCR) in various swabs, lesion materials and serum. In a non-structural protein (NSP) in-house ELISA (NSP-ELISA-IH), one commercial ELISA (NSP-ELISA-PR) and a commercial antibody NSP pen side test, only deer 1103 showed positive results from day post-inoculation (dpi) 14 onwards. Two other NSP-ELISAs detected anti-NSP serum antibodies with lower sensitivity. It also showed rising antibody levels in the virus neutralization test (VNT), the in-house SPO-ELISA-IH and the commercial SPO-ELISA-PR at dpi 9, and in another two commercial SPO-ELISAs at dpi 12 (SPO-ELISA-IV) and dpi 19 (SPO-ELISA-IZ), respectively. Six of the red deer that had been rRT-PCR and antibody negative were re-inoculated intramuscularly with the same O-serotype FMDV at dpi 14. None of these animals became rRT-PCR or NSP-ELISA positive, but all six animals became positive in the VNT, the in-house SPO-ELISA-IH and the commercial SPO-ELISA-PR. Two other commercial SPO-ELISAs were less sensitive or failed to detect animals as positive. The rRT-PCRs and the four most sensitive commercial ELISAs that had been used for the experimentally inoculated deer were further evaluated for diagnostic specificity (DSP) using 950 serum samples and 200 nasal swabs from non-infected animals. DSPs were 100% for the rRT-PCRs and between 99.8 and 100% for the ELISAs.

Differential expression of psoriasin messenger RNA between in situ and invasive human breast carcinoma.

The mRNA encoding the calcium-binding protein psoriasin was identified as being more highly expressed in the in situ versus the invasive component of the same breast tumor. Reverse transcription-PCR analysis of total RNA extracted from three independent cases of ductal carcinoma in situ of the comedo type and three cases of high-grade invasive ductal carcinoma revealed a detectable level of psoriasin mRNA expression in the in situ lesions only. Similar analysis performed on total RNA extracted from frozen sections of 32 independent breast samples, representing a continuum from normal to invasive tumor, confirmed high psoriasin expression in ductal carcinoma in situ of the comedo type only. The possible functional role of the psoriasin protein in breast tumor cells remains to be determined.

Expression of lumican in human breast carcinoma.

Lumican mRNA has been identified as being differentially expressed between different regions of the same human breast tumor. In situ hybridization study of 26 independent breast tumors confirmed the presence of lumican mRNA in fibroblast-like cells within stroma and showed a significant increase of its expression in tumor compared to adjacent normal stroma (P < 0.001). Higher lumican expression was associated with higher tumor grade, lower estrogen receptor levels in the tumor, and younger age of the patients (P < 0.05). Reverse transcription-PCR analysis of total RNA extracted from 19 independent breast tissues exhibiting lesions that are thought to parallel tumor progression also suggests that this proteoglycan is differentially expressed during tumor progression.

Oxaliplatin-containing Preoperative Therapy in Locally Advanced Rectal Cancer: Local Response, Toxicity and Long-term Outcome.

AIMS: This non-randomised study was undertaken to examine oxaliplatin as possibly an intensifying component of sequential neoadjuvant therapy in locally advanced rectal cancer for improved local and metastatic outcome. MATERIALS AND METHODS: Ninety-seven patients (57 T2-3 cases, 40 T4 cases) received two cycles of the Nordic FLOX regimen (oxaliplatin 85 mg/m(2) day 1 and bolus 5-fluorouracil 500 mg/m(2) and folinic acid 100 mg days 1 and 2) before long-course chemoradiotherapy with concomitant oxaliplatin and capecitabine, followed by pelvic surgery. Treatment toxicity, local tumour response and long-term outcome were recorded. RESULTS: Good histologic tumour regression was obtained in 72% of patients. Implementing protocol-specific dose adjustments, tolerance was acceptable and 95% of patients received the total prescribed radiation dose. Estimated 5 year progression-free and overall survival were 61% and 83%, respectively. T4 stage was associated with an inferior local response rate, which again was highly associated with impaired long-term outcome. CONCLUSIONS: In this cohort of rectal cancer patients dominated by T4 and advanced T3 cases given sequential oxaliplatin-containing preoperative therapy with acceptable toxicity, high tumour response rates and overall survival were obtained, consistent with both local and systemic effects. However, tumour response and long-term outcome remained inferior for a significant number of T4 cases, suggesting that the T4 entity is biologically heterogeneous with subgroups of patients eligible for further individualisation of therapy.

Prognostic factors in patients with symptomatic spinal metastases and normal neurological function.

AIMS: To evaluate potential prognostic factors for predicting survival after radiotherapy in patients with painful spinal metastases and normal neurological function. MATERIALS AND METHODS: In total, 173 patients were included. The following prognostic factors were assessed: primary cancer site, age, gender, albumin and haemoglobin levels, Karnofsky performance status (KPS), analgesic use, pain intensity, number of extraspinal bone metastases and visceral metastases, presence of tumour-conditioned spinal canal stenosis and metastatic spinal cord compression, and extension of spinal metastatic disease on magnetic resonance imaging (MRI). Ongoing systemic treatment, use of bisphosphonates and response to radiotherapy were also evaluated. A simple scoring system for predicting survival was used. RESULTS: The following predictive factors were found to be significant in multivariate analysis: primary cancer site, KPS, albumin level, number of visceral metastases and analgesic use. Three survival groups were proposed. The overall survival probabilities for groups 1-3 were 13, 46 and 94% at 6 months; 4, 28 and 79% at 12 months, respectively. The median survival times for groups 1-3 were 2.1, 5.5 and 24.9 months, respectively (P < 0.001). CONCLUSION: The pretreatment albumin level was a significant prognostic indicator for survival. Similarly, the primary cancer site, KPS and number of visceral metastases were associated with survival; these findings were consistent with the results of previous studies. The pretreatment analgesic use was significant using the univariate and multivariate analyses and this factor can be verified in future trials. Self-reported pain intensity, pain response to radiotherapy and MRI findings did not influence survival times.

MRI volumetry for prediction of tumour response to neoadjuvant chemotherapy followed by chemoradiotherapy in locally advanced rectal cancer.

OBJECTIVE: To investigate if MRI-assessed tumour volumetry correlates with histological tumour response to neoadjuvant chemotherapy (NACT) and subsequent chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC). METHODS: Data from 69 prospectively enrolled patients with LARC receiving NACT followed by CRT and radical surgery were analysed. Whole-tumour volumes were contoured in T2 weighted MR images obtained pre-treatment (VPRE), after NACT (VNACT) and after the full course of NACT followed by CRT (VCRT). VPRE, VNACT and tumour volume changes relative to VPRE, ΔVNACT and ΔVCRT were calculated and correlated to histological tumour regression grade (TRG). RESULTS: 61% of good histological responders (TRG 1-2) to NACT followed by CRT were correctly predicted by combining VPRE < 10.5 cm(3), ΔVNACT > -78.2% and VNACT < 3.3 cm(3). The highest accuracy was found for VNACT, with 55.1% sensitivity given 100% specificity. The volume regression after completed NACT and CRT (VCRT) was not significantly different between good and poor responders (TRG 1-2 vs TRG 3-5). CONCLUSION: MRI-assessed small tumour volumes after NACT correlated with good histological tumour response (TRG 1-2) to the completed course of NACT and CRT. Furthermore, by combining tumour volume measurements before, during and after NACT, more good responders were identified. ADVANCES IN KNOWLEDGE: MRI volumetry may be a tool for early identification of good and poor responders to NACT followed by CRT and surgery in LARC in order to aid more individualized, multimodal treatment.

Inhibition of evoked C-fibre responses in the dorsal horn after contralateral intramuscular injection of capsaicin involves activation of descending pathways.

In this study extracellular recordings of nociceptive dorsal horn neurones driven by electrical stimulation of the sciatic nerve were performed in intact urethane-anaesthetized Sprague-Dawley rats. Spikes 0-40, 40-250 and 250-800 ms after stimulus were defined as A- and C-fibre responses and post-discharge, respectively, and the effect of 200 microg capsaicin (8-methyl-N-vanillyl-6-noneamide) injected into the contralateral gastrocnemius-soleus muscle was investigated. In most cells tested, regardless of the size or location of their receptive fields, the injection of capsaicin caused a clear inhibition of the electrically evoked C-fibre responses. In animals with intact descending pathways the mean C-fibre response was inhibited to 51% of baseline 15 min after injection of capsaicin. In contrast, when capsaicin was given during cold block of the spinal cord between the brainstem and the site of recording in the dorsal horn, the same response was inhibited to 91% of baseline. A significant interaction between cold block and capsaicin was detected. We conclude that stimulation of capsaicin-sensitive afferents in the deep tissue in the hind limb can inhibit the electrically evoked C-fibre responses in the dorsal horn by activating inhibitory descending projections from higher centres. The model presented here may be an important tool for further investigations of the endogenous descending antinociceptive system.

Different role of 5-HT1A and 5-HT2 receptors in spinal cord in the control of nociceptive responsiveness.

The effects of the 5-hydroxytryptamine type-2 (5-HT2) receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT1A agonist (+)-8-hydroxy-2-(di-n-propylamino)-tetralin [(+)-8-OH-DPAT] on nociceptive responsiveness were compared in mice. Intrathecal administration of DOI (5-20 micrograms) produced a dose-dependent behavioural syndrome, consisting of biting or licking, directed towards the caudal part of the body and reciprocal hindlimb scratching. However, (+)-8-OH-DPAT (5-20 micrograms) did not produce the biting and scratching behaviour. The response to DOI (20 micrograms) was reversed by treatment with the substance P receptor antagonist, [D-Arg1, D-Trp7,9, Leu11]-SP (Spantide) (5 micrograms). The tail-flick reflex was markedly depressed 5-20 min after administration of (+)-8-OH-DPAT; DOI did not change the tail-flick reflex after 5 min but significantly inhibited the reflex response 10-20 min after injection. The data show that stimulation of 5-HT2 receptors, but not 5-HT1A receptors, induced a behavioural syndrome, which may reflect activation of nociceptive pathways. The tail-flick reflex was more markedly inhibited by stimulation of 5-HT1A than 5-HT2 receptors. Accordingly, 5-HT2 and 5-HT1A receptors seem to have a different function in the modulation of nociceptive responsiveness in the mouse.

Antinociceptive effect of intrathecally-administered desipramine and zimelidine in rats.

The effect of intrathecally (i.th.) administered desipramine and zimelidine, in doses of 5, 10 and 50 micrograms, were investigated in the tail-flick test with simultaneous measurement of the temperature of the tail skin and in the increasing temperature hot-plate test. A constant negative correlation between the temperature of the tail skin and tail-flick latency, as described previously, was found. For all doses tested, desipramine induced longer tail-flick latencies, 10 min after injection than vehicle and the temperature of the tail skin tended to increase less in this group than in controls. After adjustment of the tail-flick latencies for the changes in the temperature of the tail skin, an antinociceptive effect of desipramine was still found. For zimelidine, only the largest dose (50 micrograms) was found to be antinociceptive, after adjustment for the tail skin temperature. In the increasing temperature hot-plate test, no antinociceptive effect of these antidepressants was found. For desipramine and zimelidine, the effect in the tail-flick test, 10 min after injection, indicates that the antinociceptive effect of these drugs may have, at least partly, a spinal site of action. In the increasing temperature hot-plate test, the response is integrated supraspinally. This may partly explain the lack of effect in this test when desipramine and zimelidine were administered intrathecally.

Desipramine in small doses induces antinociception in the increasing temperature hot-plate test, but not in the tail-flick test.

The data reported for the antinociceptive effect of tricyclic antidepressants are conflicting. In this investigation, the effect of acute intraperitoneal (i.p.) administration of desipramine (2 and 5 mg/kg) was studied in rats, using the tail-flick test with simultaneous measurement of tail-skin temperature, and the increasing temperature hot-plate test. A constant negative correlation between tail-flick latency and tail-skin temperature, as described earlier, was also found in this study. Different ambient temperatures influenced the results of the tail-flick test. At an ambient temperature of 24-25 degrees C, desipramine gave rise to an apparent antinociception in the tail-flick test, which was found to be caused by a relative fall in tail-skin temperature. At 21-22 degrees C, no change in tail-flick latency was found after the administration of desipramine. In the increasing temperature hot-plate test, however, a dose-dependent antinociceptive effect of desipramine was observed at both ambient temperatures. The strong influence of moderate differences in ambient temperature on the results of the tail-flick test may explain some of the conflicting results reported in the literature. Whenever this test is used, the temperature of the tail should be recorded and taken into account in the evaluation of the data.

Reduction of NMDA-induced behaviour after acute and chronic administration of desipramine in mice.

The mechanisms of the antinociceptive effect of desipramine (DMI) are only partly known. It is generally accepted that excitatory amino acids act as neurotransmitters in primary nociceptive fibres and recent in vitro studies have shown an interaction between tricyclic antidepressants and the N-methyl-D-aspartic acid (NMDA) receptor complex. In this study, the modulatory effect of DMI on the biting and scratching behaviour induced by intrathecal (i.th.) administration of NMDA (0.25 nmol) was investigated. Desipramine was administered acutely, either intrathecally (0.7-35 micrograms) or intraperitoneally (i.p., 10 mg/kg), or chronically in the drinking water (0.15 g/l) for 3 weeks. The NMDA-induced behaviour was significantly reduced both after acute and chronic administration of DMI. Several studies have shown a functional upregulation of the 5-HT1A receptor after chronic treatment with DMI. The activation of this receptor using the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), leads to a reduction in NMDA-induced behaviour. Using the 5-HT1A antagonist NAN-190 (10 micrograms, i.th.), the effect of chronic administration of DMI on the NMDA-induced behaviour was reversed. However, NAN-190 also increased NMDA-induced behaviour in the control group, suggesting that a tonic inhibition of this behaviour, mediated by the 5-HT1A receptor, may exist. These findings indicate that DMI may reduce glutaminergic transmission at the spinal NMDA receptor. As this receptor is central in spinal nociceptive transmission, this could be one mechanism for the antinociceptive effect of DMI.

Changes in nociception after lesions of descending serotonergic pathways induced with 5,6-dihydroxytryptamine. Different effects in the formalin and tail-flick tests.

Intrathecal administration of 5,6-dihydroxytryptamine (5,6-DHT) in mice selectively lesioned descending serotonergic pathways. Nociception was evaluated 3 days after injection of 5,6-DHT using the tail-flick and formalin tests. In the tail-flick test shortened latencies were found in the lesioned animals. In contrast, the initial behavioural response (0-15 min) to formalin was reduced, while the late response (15-40 min) was not altered. Fourteen days after intrathecal administration of 5,6-DHT the changes in nociception, both in the tail-flick and in the formalin test, had returned to the control level. These findings support the contention that the raphe-spinal serotonergic system participates in the tonic regulation of nociception in the spinal cord. Apparently this system tonically inhibits spinal nociceptive reflexes, but tonically enhances the initial behavioural responses to noxious chemical stimulation, as measured with the formalin test.

Desipramine, administered chronically, influences 5-hydroxytryptamine1A-receptors, as measured by behavioral tests and receptor binding in rats.

The 5-hydroxytryptamine1A (5-HT1A) receptor subtype seems to be of importance in the pathogenesis of depression and in the mode of action of antidepressants. In this study, behavioural experiments were performed in rats after oral administration of desipramine for 18-20 days, followed by an acute injection of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), either systemically or intrathecally. Chronic administration of desipramine prolonged the behavioural 5-HT syndrome in the animals injected systemically with 8-OH-DPAT. Treatment with desipramine was also found to potentiate and prolong the antinociceptive effect of an acute injection, systemically or intrathecally, of 8-OH-DPAT in the increasing temperature hot plate test. After systemic administration of 8-OH-DPAT, the colonic temperature was lowered similarly in the desipramine-treated group and in controls, whereas an intrathecal injection of 8-OH-DPAT resulted in a fall in the colonic temperature in the desipramine-treated group only. In vitro receptor binding studies, using [3H]8-OH-DPAT as the ligand, showed a statistically significant reduction of Kd and Bmax in the frontal cortex and of Kd in the spinal cord, after treatment with desipramine. No changes of Kd and Bmax were found in the hippocampus after this treatment. Thus, desipramine, administered chronically, resulted in a functional up-regulation of the 5-HT1A-receptors, both spinally and supraspinally, whereas in the in vitro receptor binding, a slight down-regulation or no change was found. It seems therefore that the results of in vitro receptor binding studies do not necessarily reflect the functional state of the neuronal system.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic administration of desipramine and zimelidine changes the behavioural response in the formalin test in rats.

In studies of the effect on nociception of chronic administration of antidepressants, the stress of the injections may influence the results. In this experiment, desipramine or zimelidine were administered in the drinking water of rats, in a concentration yielding a dose of approximately 8 mg/kg/24 hr. Desipramine, given both for a short time (24 hr) and chronically (14 days), induced antinociception in the increasing temperature hot-plate test; zimelidine did not significantly influence the results of this test. In the tail-flick test, neither short-term nor chronic administration of these antidepressants had any effect on nociception, when correction was made for the changes in the temperature of the tail skin. In the formalin test, nine behavioural categories were scored for 1 hr and the data were treated statistically, using a multivariate analysis. Chronic administration of desipramine increased nociceptive behaviour during the first 10 min of the test. Desipramine and, to a lesser extent, zimelidine, changed the response in the late phase (10-60 min), showing less focussed pain-related behaviour (jerks and shaking, licking and biting of the injected paw) and more non-focussed pain-related behaviour (activity states with elevation or protection of the injected paw). It was concluded that desipramine is antinociceptive in the increasing temperature hot-plate test. Desipramine and zimelidine, administered chronically, modify the late phase of the formalin test towards less focussed pain-related behaviour, suggesting an antinociceptive effect. Multivariate analysis of the data of the formalin test seemed to be of value for the interpretation of the data.