Biomedical subjects
N A Martin
Publications and source records attributed to N A Martin.
Novel CCM1 mutation in a patient with paraparesis and thoracic cord cavernous malformation.
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Symptomatic Rathke's cleft cysts: a report of 24 cases.
We review the clinical, hormonal and imaging features of 24 consecutive patients with symptomatic Rathke's cleft cysts (RCCs), and assess the long-term effectiveness and complications of transsphenoidal cyst removal. Out of 250 consecutive patients, 24 (10%) underwent endonasal transsphenoidal surgery for RCC; 19 (79%) were women. Symptoms at presentation included headaches (83%), hyperprolactinemia (38%), central hypothyroidism (21%), galactorrhea (13%), diabetes insipidus (13%), IGF-1 deficiency (13%), central adrenal insufficiency (8%) and visual loss (8%). In total, 37% of women had irregular menses and 60% of men sexual dysfunction and hypogonadism. Two girls presented with precocious puberty. Cyst size varied from 7 to 25 mm. Fifteen (60%) had a suprasellar component. Initial and 3-month post-operative imaging revealed complete cyst resection in 23 of 24 patients. Headaches resolved in 65% of subjects and visual loss resolved in both patients who presented with this symptom. Of those presenting with endocrinopathy, 56% had improvement of at least one anterior pituitary axis; two subjects (8%), both with suprasellar RCC, developed a new hormone deficiency post-operatively and two sujects young girls, (8%) had RCC recurrence, one at 36 months after surgery, requiring a second operation, and the other had a small asymptomatic recurrence 6 months after surgery. In conclusion, RCC accounts for 10 % of surgically treated sellar and suprasellar masses. Headache, hyperprolactinemia, menstrual irregularities and sexual dysfunction are common presenting symptoms. Simple cyst removal via a transsphenoidal approach offers a safe and effective treatment. Cyst recurrence may be more common in children.
Assessment of cerebral blood flow by means of blood-flow-volume measurement in the internal carotid artery: comparative study with a 133xenon clearance technique.
BACKGROUND AND PURPOSE: We sought to evaluate a new, angle-independent ultrasonic device for assessment of blood flow volume (BFV) in the internal carotid artery (ICA). METHODS: Nineteen patients and 4 healthy volunteers were enrolled in a comparative study conducted in the Care Unit of the Division of Neurosurgery at UCLA Medical Center. All patients had been admitted because of severe brain injury: 15 patients with severe head trauma (Glasgow Coma Scale score< or =8) and 4 patients with subarachnoid hemorrhage due to aneurysm rupture. In all patients and subjects, cerebral blood flow (CBF) values obtained with the 133xenon-clearance technique were compared with BFV measurements in the ipsilateral ICA. RESULTS: Hemispheric CBF values showed a close and linear correlation with BFV measurements (r=0.76, P<0.0001). Global CBF values showed a higher correlation with the total BFV value obtained from both ICAs (r=0.84, P<0.0001). With 37 mL x min(-1) x 100 g(-1) as a cutoff value for the ischemic range, a BFV value of 220 mL/min would yield a positive predictive value of 91.7% and a negative predictive value of 82.6% (sensitivity 73.3%, specificity 95%). Conversely, BFV sensitivity and specificity were 60% and 96%, respectively, for the hyperemic range defined by a CBF value >55 mL x min(-1) x 100 g(-1) (positive predictive value of 85.7% and negative prediction value of 85.7%). CONCLUSIONS: BFV measurements with this new technology proved to accurately correlate with CBF values evaluated by the 133xenon-clearance technique. These results support the implementation of this technique for bedside assessment of cerebral hemodynamics in critically ill neurosurgical patients.
Acute seizures after intracerebral hemorrhage: a factor in progressive midline shift and outcome.
OBJECTIVE: To determine whether early seizures that occur frequently after intracerebral hemorrhage (ICH) lead to increased brain edema as manifested by increased midline shift. METHODS: A total of 109 patients with ischemic stroke (n = 46) and intraparenchymal hemorrhage (n = 63) prospectively underwent continuous EEG monitoring after admission. The incidence, timing, and factors associated with seizures were defined. Serial CT brain imaging was conducted at admission, 24 hours, and 48 to 72 hours after hemorrhage and assessed for hemorrhage volume and midline shift. Outcome at time of discharge was assessed using the Glasgow Outcome Scale score. RESULTS: Electrographic seizures occurred in 18 of 63 (28%) patients with ICH, compared with 3 of 46 (6%) patients with ischemic stroke (OR = 5.7, 95% CI 1.4 to 26.5, p < 0.004) during the initial 72 hours after admission. Seizures were most often focal with secondary generalization. Seizures were more common in lobar hemorrhages but occurred in 21% of subcortical hemorrhages. Posthemorrhagic seizures were associated with neurologic worsening on the NIH Stroke Scale (14.8 vs 18.6, p < 0.05) and with an increase in midline shift (+ 2.7 mm vs -2.4 mm, p < 0.03). There was a trend toward increased poor outcome (p < 0.06) in patients with posthemorrhagic seizures. On multivariate analysis, age and initial NIH Stroke Scale score were independent predictors of outcome. CONCLUSION: Seizures occur commonly after ICH and may be nonconvulsive. Seizures are independently associated with increased midline shift after intraparenchymal hemorrhage.
The discovery of viral hepatitis: a military perspective.
Viral hepatitis is one of the most common infectious diseases and over the years the jaundice associated with it has been known by many names. Several viruses are now known to cause hepatitis in humans, but sixty years ago, these viruses were unknown. In the years before and during the Second World War, there emerged a significant understanding of the clinical and epidemiological nature of the disease due to the dedicated efforts of doctors and scientists around the world. By the end of the war years, the discrete entities of Hepatitis A and B had been identified and preventative measures were proving to be effective. However, the bane of viral hepatitis was far from being resolved.
Is CPP therapy beneficial for all patients with high ICP?
Induced blood pressure elevation has become a popular treatment for intracranial hypertension. However, there remains a concern that in some patients blood pressure elevation will further elevate ICP. This study was conducted to test the hypothesis that increasing MAP decreases ICP. A total of 47 studies were performed on 23 intubated patients with head injury. MAP and SjvO2 were continuously monitored. MAP was raised significantly by 13.8 (5.9) mmHg (t-test; p < 0.0001) using phenylephrine infusion. The percent change ICP per mmHg increase in MAP (% delta ICP/mm Hg MAP) was calculated. Pearson correlation coefficient, t-test and logistic regression analysis were used for statistical evaluation. Increasing MAP resulted in a decrease in ICP in 38.3% and in an increase in ICP in 61.7% out of 47 studies. The following characteristics were seen in patients in whom a decrease in ICP was associated with an increase in MAP: High GCS (r = -0.61; p = 0.004) and low SjvO2 ((2 = 4.89; p = 0.027). In patients with lower GCS and high SjvO2 an increase in MAP resulted in an increase in ICP. We concluded that in the majority of studies increasing MAP was followed by an increase in ICP. CPP therapy has a selective indication in patients with high GCS, low SjvO2 and increased ICP.
Metabolic suppressive therapy as a treatment for intracranial hypertension--why it works and when it fails.
Thirty years after its first description metabolic suppressive therapy is still controversial in patients with intractable intracranial hypertension. In this study high dose propofol was used to induce metabolic suppression. The effects on intracranial pressure (ICP) and the cerebral metabolic rates for oxygen and glucose (CMRO2 and CMRGlc) are reported. A total of 28 studies were performed on 14 head injured patients. A Xenon133 cerebral blood flow (CBF) and a CO2-reactivity (CO2R) test were performed prior to induction of metabolic suppression. The following parameters were continuously monitored: EEG, etCO2, SjvO2, ICP, MAP and bilateral MCA flow velocity (VMCA). PCO2 was obtained before and during propofol-induced EEG burst-suppression in arterial and jugular-venous blood. CMRO2, CMRGlc and Metabolic Ratio (MR = CMRO2/CMRGlc) were calculated. MR < 0.6 was defined as relative hyperglycolysis. ICP decreased by 24.1 +/- 29.0% during burst-suppression. Arterial, jugular-venous and etCO2 also decreased. Multiple regression analysis revealed that CO2 was the strongest predictor for ICP. Lower baseline ICP and normal CO2 reactivity were predictors for normal metabolic suppression reactivity. In studies with normal metabolic ratio, ICP reduction was associated with a reduction in CMRO2. In studies with hyperglycolysis, ICP reduction was poor but CMRGlc decreased significantly. In conclusion, intact CO2R, normal or only moderately elevated ICP and normal MR are predictive of ICP reduction with high dose propofol after head injury.
Can hyperventilation improve cerebral microcirculation in patients with high ICP?
Gosling's pulsatility index (PI) is generally thought to reflect cerebrovascular resistance. Hyperventilation and increased intracranial pressure (ICP) usually increase PI. In this study, the effect of hyperventilation on PI was assessed in head injured patients with and without elevated ICP. A total of 73 hyperventilation studies were conducted on 20 intubated TBI patients. EtCO2, ICP, MCA flow velocity and MCA PI bilaterally were recorded simultaneously. Hemispheric CO2-Reactivity (hCO2R) was calculated. Only studies with a baseline ICP < 15 or > 30 mm Hg were included for analysis. With hyperventilation pCO2 decreased on average from 33.54.2 to 26.84.8 mmHg. PI increased significantly in patients with baseline ICP < 15 mmHg (11.8%; p < 0.0001) but decreased significantly if baseline ICP was > 30 mm Hg (12.21%; p = 0.0013). High baseline ICP, low initial GCS and impaired hCO2R were associated with the decrease of PI. Hyperventilation unexpectedly reduced PI in patients with high ICP. Because decreased PI suggests decreased CVR, it is postulated that hyperventilation in the setting of raised ICP improves cerebral microcirculation.
Delayed increase in extracellular glycerol with post-traumatic electrographic epileptic activity: support for the theory that seizures induce secondary injury.
Early post-traumatic seizures occur commonly and may have adverse clinical consequences. In order to determine the significance of post-traumatic seizures, we performed a prospective assessment of the consequences of epileptic activity by assessing the change in extracellular glycerol levels. Glycerol is a marker of cellular membrane breakdown. Thirteen patients underwent combined electroencephalography (EEG) and cerebral microdialysis monitoring. Two patients had seizures on EEG with associated delayed elevations of glycerol associated with the seizure activity. Higher mean levels of glycerol were present in those patients with seizures compared to those without seizures (p < 0.001). Preliminary evidence suggests that post-traumatic seizures lead to additional membrane injury as reflected by elevated extracellular glycerol levels.
Diffusion-perfusion MR evaluation of perihematomal injury in hyperacute intracerebral hemorrhage.
BACKGROUND: It has been suggested that a zone of perihematomal ischemia analogous to an ischemic penumbra exists in patients with primary intracerebral hemorrhage (ICH). Diffusion-perfusion MRI provides a novel means of assessing injury in perihematomal regions in patients with ICH. OBJECTIVE: To characterize diffusion-perfusion MRI changes in the perihematomal region in patients with hyperacute intracerebral hemorrhage. METHOD: Twelve patients presenting with hyperacute, primary ICH undergoing CT scanning and diffusion-perfusion MRI within 6 hours of symptom onset were reviewed. An automated thresholding technique was used to identify decreased apparent diffusion coefficient (ADC) values in the perihematomal regions. Perfusion maps were examined for regions of relative hypo- or hyperperfusion. RESULTS: Median baseline NIH Stroke Scale score was 17 (range, 6 to 28). Median hematoma volume was 13.3 mL (range, 3.0 to 74.8 mL). MRI detected the hematoma in all patients on echo-planar susceptibility-weighted imaging and in all seven patients imaged with gradient echo sequences. In six patients who underwent perfusion imaging, no focal defects were visualized on perfusion maps in tissues adjacent to the hematoma; however, five of six patients demonstrated diffuse ipsilateral hemispheric hypoperfusion. On diffusion imaging, perihematomal regions of decreased ADC values were identified in three of 12 patients. All three subsequently showed clinical and radiologic deterioration. CONCLUSIONS: A rim of perihematomal decreased ADC values was visualized in the hyperacute period in a subset of patients with ICH. The presence of a rim of decreased ADC outside the hematoma correlated with poor clinical outcome. Although perfusion maps did not demonstrate a focal zone of perihematomal decreased blood flow in any patient, most patients had ipsilateral hemispheric hypoperfusion.
Temporal spatial differences observed by functional MRI and human intraoperative optical imaging.
Pre-operative functional magnetic resonance imaging (fMRI), cortical evoked potentials (EPs) and intraoperative optical imaging of intrinsic signals (iOIS) were employed to relate the temporal-spatial characteristics of sensorimotor responses in human brain. Peripheral somasthetic stimulation (2 s) was provided either by a 110 Hz finger vibrator or transcutaneous median nerve stimulation in eight patients undergoing neurosurgical procedures. Each technique provided unique spatial patterns and temporal response profiles. EPs and iOIS activities were observed over the surface of pre- and post-central gyri (at the level of the superior genu) with very similar spatial distributions. In contrast, fMRI spatial distributions depended upon the model used for statistical correlation analysis. Using a monophasic response model, fMRI primarily localized within the central sulcus and did not demonstrate large signal changes over the pre- and post-central gyri (areas with iOIS/EP activity). However, as initial negative responses were incorporated into the response model, fMRI progressively localized closer to the iOIS and somatosensory EP maps. Temporally, responses to single stimuli differed between the fMRI and iOIS techniques. Using a monophasic model for fMRI analysis, the total fMRI response was delayed by 2--3 s relative to iOIS. As initial negative responses were incorporated in the analysis, the fMRI time course developed temporal characteristics similar to iOIS. Ultimately, when fMRI time courses were examined over pixels co-localizing with iOIS activation (without using statistical correlation analysis), the fMRI temporal profile included an initial decrease in signal (an initial dip) that closely resembled the time course of iOIS response. This is the first study to experimentally co-localize (temporally and spatially) iOIS and fMRI signals in human subjects. The spatial/temporal differences in this study likely reflect the capillary versus venous contributions of iOIS and fMRI, respectively. The temporal/spatial co-localization of the iOIS signal and the fMRI initial dip suggests the initial fMRI dip and the iOIS signal may result from similar physiologic events.
Transcranial Doppler pulsatility indices as a measure of diffuse small-vessel disease.
BACKGROUND AND PURPOSE: Elevation in pulsatility indices (PIs) as measured by transcranial Doppler (TCD) have been postulated to reflect downstream increased vascular resistance caused by small-vessel ischemic disease. METHODS: The authors retrospectively compared TCD PIs and magnetic resonance imaging (MRI) manifestations of small-vessel disease in 55 consecutive patients who underwent TCD studies and brain MRI within 6 months of each other during a 2-year period. RESULTS: Correlations between TCD middle cerebral artery PIs and MRI measures were as follows: periventricular hyperintensity (PVH) = 0.52 (P < .0001), deep white matter hyperintensity (DWMH) = 0.54 (P < .0001), lacunar disease = 0.31 (P = .02), and combined PVH/DWMH/lacunes = 0.54 (P < .0001). Correlation between pontine ischemia and vertebrobasilar PIs was 0.46 (P = .0004). Univariate analysis showed that age, elevated PI, and hypertension strongly correlated with white matter disease measures. After adjusting for these factors in a multivariate Poisson regression analysis, PI remained an independent predictor of white matter disease. Receiver operator curve analyses identified PI cut points that allowed discrimination of PVH with 89% sensitivity and 86% specificity and discrimination of DWMH with 70% sensitivity and 73% specificity. CONCLUSIONS: Elevation in PIs as measured by TCD shows strong correlation with MRI evidence of small-vessel disease. TCD may be a useful physiologic index of the presence and severity of diffuse small-vessel disease.
Interaction of co-expressed mu- and delta-opioid receptors in transfected rat pituitary GH(3) cells.
mu- and delta-Opioid agonists interact in a synergistic manner to produce analgesia in several animal models. Additionally, receptor binding studies using membranes derived from brain tissue indicate that interactions between mu- and delta-opioid receptors might be responsible for the observation of multiple opioid receptor subtypes. To examine potential interactions between mu- and delta-opioid receptors, we examined receptor binding and functional characteristics of mu-, delta-, or both mu- and delta-opioid receptors stably transfected in rat pituitary GH(3) cells (GH(3)MOR, GH(3)DOR, and GH(3)MORDOR, respectively). Saturation and competition binding experiments revealed that coexpression of mu- and delta-opioid receptors resulted in the appearance of multiple affinity states for mu- but not delta-opioid receptors. Additionally, coadministration of selective mu- and delta-opioid agonists in GH(3)MORDOR cells resulted in a synergistic competition with [(3)H][D-Pen(2,5)]enkephalin (DPDPE) for delta-opioid receptors. Finally, when equally effective concentrations of [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) and two different delta-opioid agonists (DPDPE or 2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a alpha-octahydroquinolino-[2,3,3-g]-isoquinoline; TAN67) were coadministered in GH(3)MORDOR cells, a synergistic inhibition of adenylyl cyclase activity was observed. These results strongly suggest that cotransfection of mu- and delta-opioid receptors alters the binding and functional characteristics of the receptors. Therefore, we propose that the simultaneous exposure of GH(3)MORDOR cells to selective mu- and delta-opioid agonists produces an interaction between receptors resulting in enhanced receptor binding. This effect is translated into an augmented ability of these agonists to inhibit adenylyl cyclase activity. Similar interactions occurring in neurons that express both mu- and delta-opioid receptors could explain observations of multiple opioid receptor subtypes in receptor binding studies and the synergistic interaction of mu- and delta-opioids in analgesic assays.
Carbon dioxide reactivity, pressure autoregulation, and metabolic suppression reactivity after head injury: a transcranial Doppler study.
OBJECT: Contemporary management of head-injured patients is based on assumptions about CO2 reactivity, pressure autoregulation (PA), and vascular reactivity to pharmacological metabolic suppression. In this study, serial assessments of vasoreactivity of the middle cerebral artery (MCA) were performed using bilateral transcranial Doppler (TCD) ultrasonography. METHODS: Twenty-eight patients (mean age 33 +/- 13 years, median Glasgow Coma Scale score of 7) underwent a total of 61 testing sessions during postinjury Days 0 to 13. The CO2 reactivity (58 studies in 28 patients), PA (51 studies in 23 patients), and metabolic suppression reactivity (35 studies in 16 patients) were quantified for each cerebral hemisphere by measuring changes in MCA velocity in response to transient hyperventilation, arterial blood pressure elevation, or propofol-induced burst suppression, respectively. One or both hemispheres registered below normal vasoreactivity scores in 40%, 69%, and 97% of study sessions for CO2 reactivity, PA, and metabolic suppression reactivity (p < 0.0001), respectively. Intracranial hypertension, classified as intracranial pressure (ICP) greater than 20 mm Hg at the time of testing, was associated with global impairment of CO2 reactivity, PA, and metabolic suppression reactivity (p < 0.05). A low baseline cerebral perfusion pressure (CPP) was also predictive of impaired CO2 reactivity and PA (p < 0.01). Early postinjury hypotension or hypoxia was also associated with impaired CO2 reactivity (p < 0.05), and hemorrhagic brain lesions in or overlying the MCA territory were predictive of impaired metabolic suppression reactivity (p < 0.01). The 6-month Glasgow Outcome Scale score correlated with the overall degree of impaired vasoreactivity (p < 0.05). CONCLUSIONS: During the first 2 weeks after moderate or severe head injury, CO2 reactivity remains relatively intact, PA is variably impaired, and metabolic suppression reactivity remains severely impaired. Elevated ICP appears to affect all three components of vasoreactivity that were tested, whereas other clinical factors such as CPP, hypotensive and hypoxic insults, and hemorrhagic brain lesions have distinctly different impacts on the state of vasoreactivity. Incorporation of TCD ultrasonography-derived vasoreactivity data may facilitate more injury- and time-specific therapies for head-injured patients.
Surgical and endovascular treatment of spinal dural arteriovenous fistulas: long-term disability assessment and prognostic factors.
OBJECT: The authors assessed clinical outcomes of patients with treated spinal dural arteriovenous fistulas (DAVFs) and investigated prognostic factors. METHODS: Thirty consecutive patients with spinal DAVFs were treated at the authors' institution during the past 15 years: seven underwent surgery; seven underwent surgery after failed embolization: and 16 underwent embolization alone. The outcomes of gait and micturition disability, were analyzed. Follow up averaged 3.4 years (range 1 month-11.8 years). Age, duration of symptoms, pre- and postintervention magnetic resonance (MR) imaging findings, and preintervention disability were correlated with outcome. Seventeen patients (57%) experienced improved gait, 12 (40%) were unchanged, and one (3%) was worse. In 11 patients (37%) micturition function was improved, in 15 (50%) it was unchanged, and in four (13%) it was worse. Gait disability, as measured by the Aminoff-Logue Scale, was significantly improved after treatment, from 3.4+/-1.4 (average +/- standard deviation) to 2.7+/-1.5 (p = 0.007). Mean micturition disability scores decreased, but not significantly, from 1.9+/-1 to 1.6+/-1.1 (p = 0.20). Preintervention gait disability was not associated with improvement except for patients with Aminoff-Logue Scale Grade 4 disability (eight of nine improved; p = 0.024). For patients treated within 13 months of symptom onset, mean micturition disability decreased (p = 0.035). No association was found between clinical improvement and age, a symptom duration less than 30 months, or pre- and postintervention MR imaging-documented spinal cord edema. CONCLUSIONS: Spinal DAVF treatment significantly improved patients' mean gait disability score by almost one grade at last follow up. The mean micturition disability score was not significantly improved, unless treatment was performed within 13 months of symptom onset. Longer and more uniform follow-up study is needed to determine if improved and stabilized clinical outcomes are sustained.
N-butyl 2-cyanoacrylate embolization of spinal dural arteriovenous fistulae.
BACKGROUND AND PURPOSE: Because they are not well established, we investigated the technical success and recurrence rates of n-butyl 2-cyanoacrylate (NBCA) embolization of spinal dural arteriovenous fistulae (SDAVF), and assessed clinical outcomes. METHODS: We retrospectively studied all patients with SDAVF treated by NBCA embolization at our institution over an 8-year period. Gait and micturition disabilities were analyzed. Follow-up periods averaged 3.1 years (range, 1 month to 8.9 years). RESULTS: NBCA embolization was feasible in 74% (20/27) of patients. Of 20 patients who underwent embolization, initial embolization failure occurred in two (10%) and fistula occurrence in three (15%). All five patients in whom NBCA embolization failed underwent surgery. All patients who underwent embolization had either improved (55%) or unchanged (45%) gait disability at last follow-up. Seventeen (85%) patients had improved (40%) or unchanged (45%) micturition disability, but three (15%) had worsened. Mean Aminoff gait disability grade significantly decreased at last follow-up (2.4 [1.4] average [SD] vs 3.2 [1.4] [P = .0008]). Mean micturition disability grade decreased, but not significantly (1.4 [1.0] vs 1.7 [1.1] [P = .28]). CONCLUSION: NBCA embolization of SDAVF was technically feasible in 75% of patients. Initial apparent successful embolization was achieved in 90%; the fistula recurrence rate (failure to occlude the draining vein) for NBCA was 15%. Comparing favorably to surgical series, NBCA embolization of SDAVF appears efficacious, significantly improving mean gait disability by almost one grade at last follow-up. Close clinical and angiographic surveillance is mandatory. Longer and more uniform follow-up is needed to determine if clinical improvement and stabilization after NBCA embolization are sustained.
Agonist Activity of the delta-antagonists TIPP and TIPP-psi in cellular models expressing endogenous or transfected delta-opioid receptors.
A new class of highly selective delta-opioid receptor antagonists has been recently developed, termed the TIP(P) peptides. Two prototypical compounds in this class are TIPP (H-Tyr-Tic-Phe-Phe-OH) and a derivative, TIPP-psi (H-Tyr-Tic[CH2NH]-Phe-Phe-OH). Surprisingly, both TIPP and TIPP-psi demonstrated inhibition of adenylyl cyclase activity in GH3 cells transfected with delta-opioid receptors (GH3DORT), an effect normally observed by agonists. The agonist activity was delta-selective, because no inhibition occurred in wild-type GH3 or GH3MOR (mu-opioid receptor) cells. Both TIPP and TIPP-psi exhibited concentration-dependent inhibition of adenylyl cyclase activity; however, TIPP-psi was found to be less potent (IC50 = 3.97 versus 0.162 nM) and less efficacious (I(max) = 50% versus 70%) than TIPP. Pretreatment of cells with pertussis toxin attenuated the inhibition of maximally effective concentrations of TIPP and TIPP-psi, indicating the involvement of G(i)alpha/G(o)alpha G-proteins. Other delta-antagonists, naltriben, naloxone, and ICI 174864, attenuated the inhibition of adenylyl cyclase activity mediated by TIPP. Coadministration of TIPP with the selective delta-agonist [D-Pen2,5]enkephalin resulted in an additive interaction. Both TIPP and TIPP-psi exhibited significant inhibition of adenylyl cyclase activity in different GH3DORT clones expressing a 28-fold range of delta-opioid receptor densities, and in cell lines expressing endogenous (i.e., N1E115 and NG108-15) and transfected (i.e., Chinese hamster ovary-DOR and human embryonic kidney-DOR) delta-opioid receptors, with densities ranging from 0.12 to 6.67 pmol/mg. These results suggest that compounds previously thought to be purely delta-opioid receptor antagonists also demonstrate agonist activity in several in vitro models.