Nucleic acid testing (NAT) of organ donors: is the 'best' test the right test? A consensus conference report.

Nucleic acid testing (NAT) for HIV, HBV and HCV shortens the time between infection and detection by available testing. A group of experts was selected to develop recommendations for the use of NAT in the HIV/HBV/HCV screening of potential organ donors. The rapid turnaround times needed for donor testing and the risk of death while awaiting transplantation make organ donor screening different from screening blood-or tissue donors. In donors with no identified risk factors, there is insufficient evidence to recommend routine NAT, as the benefits of NAT may not outweigh the disadvantages of NAT especially when false-positive results can lead to loss of donor organs. For donors with identified behavioral risk factors, NAT should be considered to reduce the risk of transmission and increase organ utilization. Informed consent balancing the risks of donor-derived infection against the risk of remaining on the waiting list should be obtained at the time of candidate listing and again at the time of organ offer. In conclusion, there is insufficient evidence to recommend universal prospective screening of organ donors for HIV, HCV and HBV using current NAT platforms. Further study of viral screening modalities may reduce disease transmission risk without excessive donor loss.

Positive cross-match living donor kidney transplantation: longer-term outcomes.

The long-term graft outcomes after positive cross-match (PXM) living donor kidney transplantation (LDKT) are unknown and the descriptive published data present short-medium term results. We conducted a retrospective cohort study of LDKT with PXM by flow cytometry performed at our center during February 1999 to October 2006, compared to a control group, matched 1:1 for age, sex, race, retransplantation and transplant year. The PXM group was treated with a course of plasmapheresis/low-dose intravenous immunoglobulin (IVIg) preoperatively, and OKT3 or thymoglobulin induction. Both groups (n = 41 each) were comparable except for duration of end-stage renal disease (ESRD), induction, HLA mismatch and panel-reactive antibody (PRA). During the period of up to 9 years, 14 PXM and 7 controls lost their grafts (p < 0.04). Graft survival rates at 1 and 5 years were 89.9% and 69.4% for PXM group and 97.6% and 80.6% for the controls, respectively. PXM was associated with higher risk of graft loss (HR 2.6, p = 0.04; 95%CI 1.03-6.4) (t(1/2)= 6.8 years), but not with patient survival (HR 1.96, p = 0.29; 95%CI 0.6-7.0) or 1-year serum creatinine (beta= 0.06, p = 0.59 for ln (SCr); 95% CI -0.16 to 0.28). These results suggest that despite the favorable short-term results of PXM LDKT after PP/IVIg conditioning, medium-long-term outcomes are notably worse than expected, perhaps comparable to non-ECD deceased donor kidney transplantation (KT).

The Maryland aggregate pathology index: a deceased donor kidney biopsy scoring system for predicting graft failure.

Despite the common use of diagnostic pretransplant deceased donor kidney biopsy, there is no consensus on the prognostic significance of the pathologic findings. In order to assist clinicians with interpretation we analyzed 371 pretransplant biopsies and correlated the findings with graft failure. Glomerular pathology was assessed with percent glomerulosclerosis (GS), glomerular size and periglomerular fibrosis (PGF); vascular pathology with arterial wall-to-lumen ratio (WLR) and arteriolar hyalinosis and interstitial pathology with measurement of cumulative fibrosis and presence of scar. Using two-thirds of the study population as a model-development cohort, we found that biopsy features independently associated with an increased risk of graft failure were GS > or =15%, interlobular arterial WLR > or =0.5 and the presence of PGF, arteriolar hyalinosis or scar. The Maryland Aggregate Pathology Index (MAPI), was developed from these parameters and validated on the remaining one-third of the population. Five-year actuarial graft survival was 90% for kidneys with MAPI scores between 0 and 7, 63% for scores from 8 to 11 and 53% for scores from 12 to 15 (p < 0.001). We conclude MAPI may help transplant physicians estimate graft survival from the preimplantation biopsy findings, in clinical situations similar to this study population (cold ischemia over 24 h, GS < 25%).

Estimated benefits of transplantation of kidneys from donors at increased risk for HIV or hepatitis C infection.

Kidneys from organ donors who have behaviors that place them at increased risk for infection with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) are often discarded, even if viral screening tests are negative. This study compared policies that would either 'Discard' or 'Transplant' kidneys from Centers for Disease Control classified increased-risk donors (CDC-IRDs) using a decision analytic Markov model of renal failure treatment modalities. Base-case CDC-IRDs were current injection drug users (IDUs) with negative antibody and nucleic acid testing (NAT) for HIV and HCV, comprising 5% of kidney donors. Compared to a CDC-IRD kidney 'Discard' policy, the 'Transplant' policy resulted in higher patient survival, a greater number of quality-adjusted life-years (QALYs) (5.6 vs. 5.1 years per patient), more kidney transplants (990 vs. 740 transplants per 1000 patients) and lower cost of care ($60 000 vs. $71 000 per QALY). The total number of viral infections was lower with the 'Transplant' policy (13.1 vs. 14.8 infections per 1000 patients over 20 years), because the 'Discard' policy led to more time on hemodialysis, with a higher HCV incidence. We recommend that kidneys from NAT-negative CDC-IRDs be considered for transplantation since the practice is estimated to be beneficial from both the societal and individual patient perspective.

Histological findings in "incidental" intraoperative pancreas allograft biopsies.

Thirty intraoperative needle core biopsies of well-functioning pancreas allografts were performed from 2 days to 7 years posttransplantation (mean 15.4 months). Most samples (83.3%) lacked significant inflammation or fibrosis. The five patients who showed features of ongoing low-grade acute rejection experienced premature graft losses due to chronic rejection. There were no complications related to the intraoperative biopsy itself.

Intraoperative catecholamine release in brain-dead organ donors is not suppressed by administration of fentanyl.

BACKGROUND AND OBJECTIVE: Endogenous catecholamines are released in brain-dead organ donors following painful stimulation during retrieval surgery, and might be harmful to harvested organs. Our hypothesis was that inhibition of pain by fentanyl would inhibit such catecholamine release. METHODS: We tested 17 brain-dead organ donors in a randomized, placebo-controlled, double-blinded study. Blood samples for determination of epinephrine and norepinephrine concentrations were obtained before and 10 min after in take of either fentanyl 7 microg kg(-1) or an equivalent volume of placebo. Further points of measurement were taken after skin incision and sternotomy. Mean arterial pressure and heart rate at these points were recorded. RESULTS: Catecholamine concentrations rose following painful stimuli. No differences in haemodynamics, between the fentanyl and the placebo group were detectable. Epinephrine concentrations, but not those of norepinephrine, were higher in the fentanyl group, reaching significance following sternotomy. CONCLUSION: We conclude that the use of fentanyl (7 microg kg(-1)) was not effective in suppressing the catecholamine release, following painful surgical stimulation in brain-dead organ donors.

Equi-lasting doses of rocuronium, compared to mivacurium, result in improved neuromuscular blockade in patients undergoing gynecological laparoscopy : [Des doses de durée équivalente de rocuronium, comparé au mivacurium, améliorent la curarisation chez des patientes qui subissent une laparoscopie gynécologique].

PURPOSE: To compare equi-lasting doses of a short-acting (mivacurium) to an intermediate-acting (rocuronium) neuromuscular relaxant, with regard to intubating conditions, efficacy, number of maintenance doses, hemodynamic alterations, adverse events and costs, in patients undergoing laparoscopic gynecological surgery. METHODS: Sixty patients were randomly allocated to receive either 0.2 mg*kg(-1) (3 x ED(95)) mivacurium or 0.5 mg*kg(-1) (1.7 x ED(95)) rocuronium, under propofol/fentanyl anesthesia. T1, first twitch of the train-of-four (TOF) and TOF ratio (T4:T1) were used to evaluate neuromuscular block using the Relaxometer(R) mechanomyograph. The trachea was intubated when T1 was maximally suppressed. Neuromuscular block was maintained at 25% T1 with equi-lasting doses of 0.075 mg*kg(-1) mivacurium or 0.15 mg*kg(-1) rocuronium. RESULTS: Mean (min) +/- SD mivacurium onset time (1.9 +/- 0.4) was longer than that of rocuronium (1.3 +/- 0.3). This did not yield a statistical difference in intubating conditions between the two groups. Interval 25-75% T1 recovery and time to 0.8 TOF recovery were prolonged following rocuronium (11.9 +/- 3.9, 52.6 +/- 15.5 respectively) compared to mivacurium (6.7 +/- 2.3, 39.2 +/- 8.1 respectively). More patients, 22/30, required mivacurium maintenance doses compared to 14/30 patients in the rocuronium group. Arterial blood pressure declined and 13/30 patients manifested erythema following mivacurium administration. The acquisition costs of rocuronium (6.93 Euro/patient) were 23% lower compared to mivacurium (8.96 Euro/patient). CONCLUSION: Equi-lasting doses of rocuronium resulted in favourable intubating conditions more rapidly, improved hemodynamic stability, required less frequent administration of maintenance doses and were not associated with erythema, compared to mivacurium.

Superiority of portal venous drainage over systemic venous drainage in pancreas transplantation: a retrospective study.

OBJECTIVE: To compare portal and systemic venous drainage of pancreas transplants and demonstrate an immunologic and survival superiority of portal venous drainage. SUMMARY BACKGROUND DATA: Traditionally, solitary pancreas transplants have been performed using systemic venous and bladder drainage, but more recently, the advantages of enteric drainage have been well documented. Although physiologic benefits for portal venous drainage have been described, the impact of portal venous drainage, especially with solitary pancreas transplants, has yet to be determined. METHODS: Since August 1995, 280 pancreas transplants with enteric duct drainage were analyzed. One hundred and seventeen were simultaneous pancreas and kidney (SPK), 63 with systemic venous drainage (SV) and 54 with portal venous drainage (PV). The remainder were solitary transplants; 97 pancreas after kidney (PAK; 42 SV and 55 PV) and 66 transplants alone (PTA; 26 SV and 40 PV). Immunosuppressive therapy was equivalent for both groups. RESULTS: The groups were similar with respect to recipient characteristics and HLA matching. Thirty-six month graft survival for all transplants was 79% for PV and 65% for SV (P =.008). By category, SPK graft survival was 74% for PV and 76% for SV, PAK graft survival was 70% for PV and 56% for SV, and PTA graft survival was 84% for PV and 50% for SV. The rate of at least one rejection episode was also significantly higher in the SV group. At 36 months, for all pancreas transplants, the rejection rate was 21% for PV and 52% for SV (P <.0001). For SPK, rejection rates were 9% for PV and 45% for SV. For PAK, rejection rates were 16% for PV and 65% for SV, and for PTA 36% for PV and 51% for SV. The rejection rates for kidneys following SPK were also lower in the PV group (26% versus 43% for SV). Furthermore, the grades of rejection were milder in PV for all transplants (P =.017). By multivariate analysis, portal venous drainage was the only parameter that significantly affected rejection. CONCLUSION: Graft survival and rejection is superior for PV. These clinical findings are consistent with published reports of experimentally induced portal tolerance and strongly argue that PV drainage should be the procedure of choice for pancreas transplantation.

Pancreas transplantation: the histologic morphology of graft loss and clinical correlations.

BACKGROUND: Graft losses due to leaks, bleeding, thrombosis, infections, and early pancreatitis are grouped together under the category of technical failure. Among these complications, massive vascular thrombosis continues to be the most important cause of early graft loss due to technical failure. Pathological evaluation of most allografts lost early in the posttransplantation period shows vascular thrombosis with associated proportional parenchymal necrosis. The morphological findings in allografts that are considered to be lost due to technical failure has not been systematically addressed. In particular, the role of acute rejection in early graft loss has not been well studied. METHODS: Seventy-four consecutive pancreas graft pancreatectomies were studied histologically to evaluate for thrombosis (recent versus organized), type of vessel involved by thrombosis (arteries, veins, or both), acute rejection grade, chronic rejection grade, endotheliitis, transplant arteritis, coagulation necrosis, acute pancreatitis, presence of infectious organisms, transplant (obliterative) arteriopathy, neoplasia, relative proportions of alpha and beta islet cells, and immunoglobulin and complement deposition. The histological findings were correlated with donor and recipient data as well as clinical presentation. RESULTS: In 23 out of 39 grafts lost in the first 4 weeks posttransplantation, the only pathological changes found were vascular thrombosis and bland ischemic parenchymal necrosis. In these cases, no underlying vascular pathology or any other specific histological change was identified. Most of these grafts (78%) were lost in less than 48 hr and all in the first 2 weeks posttransplantation. Massive vascular thrombosis occurring in an otherwise histologically normal pancreas was the most common cause of graft loss in the first 4 weeks posttransplantation (59%). In most of the remaining cases (33%), although the clinical presentation suggested technical failure, there was clear histological evidence that the massive thrombosis resulted from vascular injury due to immune damage (acute and hyperacute rejection). Increased incidence of early graft thrombosis was seen in grafts from older donors and longer cold ischemia times. After the first month posttransplantation, graft pancreatectomies revealed a wider variety of pathological processes that included severe acute rejection, combined acute and chronic rejection, chronic rejection, and infections. Acute and chronic vascular thrombosis in large and small vessels was commonly seen at all times posttransplantation; chronic, organized thrombosis was strongly associated with chronic rejection. CONCLUSIONS: (a) Early acute thrombosis occurring in a histologically normal pancreas defines a true technical failure. This study showed that acute rejection leading to massive thrombosis, which clinically simulates technical failure, results in a significant proportion of early graft losses. (b) Systematic histological evaluation of failed grafts is absolutely necessary for the accurate classification of the cause of graft loss. (c) There is morphological evidence that chronically ongoing thrombosis is an important, common, contributing factor for late graft loss.

Nalbuphine by PCA-pump for analgesia following hysterectomy: bolus application versus continuous infusion with bolus application.

The analgesic properties of the partial agonist-antagonist nalbuphine in the postoperative period are well known. When used for patient-controlled analgesia (PCA) the effectiveness of this substance is comparable to that of morphine or tramadol. However, the optimal programme for administration of nalbuphine in PCA-pumps has not been investigated. In particular, the combination of bolus administration vs bolus administration plus continuous basal administration is disputable. We hypothesized that the administration of an extra basal rate of nalbuphine in addition to the patient- triggered bolus administration and supplemental doses of diclofenac when required, would lead to a significant improvement in analgesia, without affecting the differences in vital signs and side effects. After approvement by the institutional ethics committee, 50 female patients (ASA I or II) scheduled for elective hysterectomy were included in a prospective, single-blinded study and randomized either into bolus-continuous (BC-)group (3 mg base rate/h, 1 mg bolus, 20 min lock out) or bolus (B-)group (no base rate, 1 mg bolus, 10 min lock out). During the observation period (up to 24 h postoperative) vital parameters, extent of analgesia (10-step VAS), and vigilance (5-step scale) were registered. Groups were compared by using unpaired Student t-test. A p<0.05 was considered to be significant. No differences were found in demographic data or vital parameters (MAP, PaO2, PaCO2, respiratory rate, heart rate, peripheral SaO2) during the observation period. Vital parameters showed no pathological changes in any group. With an identical rate of requirement for diclofenac (32 and 36%), analgesia in BC-group showed a decrease in VAS from 4.28+/-2.11 to 2.04+/-1.21 and from 3.64+/-2.20 to 2.08+/-0.96 in B-group. Vigilance was only marginally diminished in both groups. No serious side effects were found in either group. The consumption of nalbuphine (mg) was significantly higher in BC-group (70.28+/-13.85 vs. 47.44+/-22.99;p =0.0002) when compared to B-group. Subjective rating of effectiveness by the patients was similar in both groups. The two administration settings of nalbuphine by PCA pump have shown to be equally effective in the treatment of postoperative pain following hysterectomy. However, as the total amount of nalbuphine was significantly lower in B-group, the use of this administration schedule should be encouraged.

Elevation of nerve growth factor and antisense knockdown of TrkA receptor during contextual memory consolidation.

We report here a series of experiments establishing a role for nerve growth factor and its high-affinity receptor TrkA in contextual memory consolidation. In all experiments, we trained rats in a novel chamber using tone and shock. Our first experiment revealed that endogenous nerve growth factor (NGF) increases in the hippocampus at a critical time during consolidation that occurs 1 week after training. NGF levels at other intervals (24 hr and 2 and 4 weeks after training) did not differ from those of naive control animals. In our second experiment, we blocked effects that NGF has at 1 week after training by infusing antisense TrkA phosphorothioate DNA oligonucleotide. Reduction of septohippocampal TrkA receptor expression selectively impaired memory consolidation for context but not for tone. Animals with antisense TrkA oligonucleotide infused into the medial septal area or CA1 of the hippocampus froze less when placed in the training chamber than did animals infused with inactive randomized oligonucleotide. At 4 weeks after training, antisense TrkA oligonucleotide had no effect on freezing. Third, we correlated levels of freezing with choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) immunohistochemistry. Antisense TrkA infused into CA1 of the hippocampus reduced cell body cross-sectional area for cholinergic cells in the medial septal area and decreased the density of hippocampal terminals labeled for ChAT and VAChT proteins. Cholinergic cell body measurements were significantly correlated with freezing. Taken together, these results indicate a role for nerve growth factor acting via the TrkA receptor on ChAT and VAChT proteins in contextual memory consolidation.

Modulation of BzATP and formalin induced nociception: attenuation by the P2X receptor antagonist, TNP-ATP and enhancement by the P2X(3) allosteric modulator, cibacron blue.

1. Exogenous ATP produces acute and localized pain in humans, and P2X receptor agonists elicit acute nociceptive behaviours in rodents following intradermal administration to the hindpaw. The predominant localization of P2X(3) mRNA in sensory neurones has led to the hypothesis that activation of P2X(3) and/or P2X(2/3) receptors contributes to nociception. 2. The local administration of the P2X receptor agonist, BzATP (100--1000 nmol paw(-1), s.c.) into the rat hindpaw produced an acute (<15 min) paw flinching response that was similar to that observed in the acute phase of the formalin (5%) test. 3. The co-administration of the potent P2X receptor antagonist, TNP-ATP (30--300 nmol paw(-1)), but not an inactive analogue, TNP-AMP, with BzATP into the rat hindpaw attenuated BzATP-induced nociception. Similarly, co-administration of TNP-ATP, but not TNP-AMP, with 5% formalin reduced both acute and persistent nociception in this test. 4. Co-administration of cibacron blue (30 and 100 nmol paw(-1)), a selective allosteric enhancer of P2X(3) and P2X(2/3) receptor activation, with BzATP (30 and 100 nmol paw(-1)) into the rat hindpaw produced significantly greater nociception as compared to the algogenic effects of BzATP alone. Intradermal co-administration of cibacron blue (30 and 100 nmol paw(-1)) with formalin (1 and 2.5%) into the rat hindpaw also produced significantly greater nociceptive behaviour as compared to formalin alone. 5. The ability of TNP-ATP and cibacron blue to respectively attenuate and enhance nociceptive responses elicited by exogenous BzATP and formalin provide further support for the hypothesis that activation of peripheral P2X(3) containing channels contributes specifically to both acute and persistent nociception in the rat.

A cost-effectiveness analysis of alternative at-home or in-laboratory technologies for the diagnosis of obstructive sleep apnea syndrome.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a common disorder that affects 2% to 9% of the population. Health care policy makers have noted increased referrals for sleep studies. OBJECTIVE: In this article, the authors conduct a cost-effectiveness analysis to determine the optimal technology for the diagnosis of OSAS using polysomnography (PSG) or partial sleep monitoring (PSM). DESIGN: The target population was a hypothetical cohort of patients suspected of having OSAS. A 2-level decision tree wasformulated that reflects all possible steps of OSAS diagnosis and therapy. The method represents a comprehensive strategy to determine which of the 2 systems-PSG or PSM-has cost advantages. The financial and operational aspects of OSAS diagnosis and therapy were analyzed. A sensitivity analysis was performed over all uncertain parameters (i.e., diagnostic agreement, data loss, and referral to therapy). RESULTS: Unattended at-home sleep monitoring was the most expensive method. The combination of 1:2 PSG and attended PSM strategy was the optimal strategy with respect tofinancing and operations. Compared to the PSG-only strategy, this combination may lead to a 10% reduction of the annual expenditure. CONCLUSION: This study provides proof of concept (under a wide range of sensitivity assumptions) that the cost of sleep study techniques can be modeled. It rejects the assumption that athome portable sleep monitoring is cost advantageous. The combination of PSG and attended PSM OSAS is the most cost-effective approach to sleep evaluation.

A high panel-reactive antibody rescue protocol for cross-match-positive live donor kidney transplants.

BACKGROUND: Alloimmunization can present a virtually insurmountable barrier to kidney transplantation. Past protocols to desensitize patients using plasmapheresis and cyclophosphamide have not been broadly applied because of the fear of complications, including high rates of immunologic failure. METHODS: Fifteen patients with a positive donor-recipient cross-match were desensitized with plasmapheresis to permit live donor (LD) transplantation under newer maintenance immunosuppressants. Pretransplant the patients received plasmapheresis three times weekly for a planned maximum of six treatments, plus intravenous hyperimmune globulin, tacrolimus, mycophenolate mofetil, and prednisone. Patients who were successfully desensitized and received transplants were given 10 days of OKT3 postoperatively. RESULTS: Eleven of the 15 patients became anti-human globulin cross-match-negative after one to five plasmapheresis treatments and underwent LD transplantation. Relatively low initial titers of donor-specific antibody were predictive of successful attainment of a negative cross-match. Few side effects and rejection episodes were observed. All transplant patients remain dialysis-free after 3-26 months of follow-up. CONCLUSION: A positive cross-match is not necessarily a contraindication to LD transplantation, especially for patients with low donor-specific alloantibody titers.

Simultaneous cadaver pancreas living-donor kidney transplantation: a new approach for the type 1 diabetic uremic patient.

OBJECTIVE: To review the authors' experience with a new approach for type I diabetic uremic patients: simultaneous cadaver-donor pancreas and living-donor kidney transplant (SPLK). SUMMARY BACKGROUND DATA: Simultaneous cadaver kidney and pancreas transplantation (SPK) and living-donor kidney transplantation alone followed by a solitary cadaver-donor pancreas transplant (PAK) have been the transplant options for type I diabetic uremic patients. SPK pancreas graft survival has historically exceeded that of solitary pancreas transplantation. Recent improvement in solitary pancreas transplant survival rates has narrowed the advantage seen with SPK. PAK, however, requires sequential transplant operations. In contrast to PAK and SPK, SPLK is a single operation that offers the potential benefits of living kidney donation: shorter waiting time, expansion of the organ donor pool, and improved short-term and long-term renal graft function. METHODS: Between May 1998 and September 1999, the authors performed 30 SPLK procedures, coordinating the cadaver pancreas transplant with simultaneous transplantation of a laparoscopically removed living-donor kidney. Of the 30 SPLKs, 28 (93%) were portally and enterically drained. During the same period, the authors also performed 19 primary SPK and 17 primary PAK transplants. RESULTS: One-year pancreas, kidney, and patient survival rates were 88%, 95%, and 95% for SPLK recipients. One-year pancreas graft survival rates in SPK and PAK recipients were 84% and 71%. Of 30 SPLK transplants, 29 (97%) had immediate renal graft function, whereas 79% of SPK kidneys had immediate function. Reoperative rates, early readmission to the hospital, and initial length of stay were similar between SPLK and SPK recipients. SPLK recipients had a shorter wait time for transplantation. CONCLUSIONS: Early pancreas, kidney, and patient survival rates after SPLK are similar to those for SPK. Waiting time was significantly shortened. SPLK recipients had lower rates of delayed renal graft function than SPK recipients. Combining cadaver pancreas transplantation with living-donor kidney transplantation does not harm renal graft outcome. Given the advantages of living-donor kidney transplant, SPLK should be considered for all uremic type I diabetic patients with living donors.

ABT-702 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin- 3-yl)pyrido[2,3-d]pyrimidine), a novel orally effective adenosine kinase inhibitor with analgesic and anti-inflammatory properties. II. In vivo characterization in the rat.

Adenosine kinase (AK; EC 2.7.1.20) is a key intracellular enzyme regulating intra-and extracellular concentrations of adenosine (ADO), an endogenous neuromodulator, antinociceptive, and anti-inflammatory autocoid. AK inhibition provides a means of potentiating local tissue concentrations of endogenous ADO, and AK inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. The effects of ABT-702, a novel, potent (IC(50) = 1.7 nM), and selective non-nucleoside AK inhibitor were examined in rat models of nociception and acute inflammation. ABT-702 was orally effective and fully efficacious to suppress nociception in a spectrum of pain models in the rat, including carrageenan-induced thermal hyperalgesia, the formalin test of persistent pain, and models of nerve injury-induced and diabetic neuropathic pain (tactile allodynia after L5/L6 spinal nerve ligation or streptozotocin injection, respectively.) ABT-702 was especially potent at relieving inflammatory thermal hyperalgesia (ED(50) = 5 micromol/kg p.o.). ABT-702 was also effective in the carrageenan-induced paw edema model of acute inflammation (ED(50) = 70 micromol/kg p.o.). The antinociceptive and anti-inflammatory effects of ABT-702 were blocked by selective ADO receptor antagonists, consistent with endogenous ADO accumulation and ADO receptor activation as a mechanism of action. The antinociceptive effects of ABT-702 were not blocked by the opioid antagonist naloxone. In addition, ABT-702 showed less potential to develop tolerance to its antinociceptive effects compared with morphine. ABT-702 had no significant effect on rotorod performance or heart rate (at 30-300 micromol/kg p.o.), mean arterial pressure (at 30-100 micromol/kg p.o.), or exploratory locomotor activity (at