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Background Opioids are the most commonly prescribed analgesics in the United States. Current guidelines have proposed education initiatives to reduce the risk of chronic opioid consumption, yet there is lack of efficacy data on such interventions. Our study evaluates the impact of perioperative opioid education on postoperative opioid consumption patterns including opioid cessation, number of pills consumed, and opioid prescription refills. Methods The MEDLINE/PubMed, Embase, Cochrane Library, Scopus, and Google Scholar databases were systematically searched for randomized controlled trials (RCTs) assessing the impact of perioperative educational interventions (using either paper- or video-based instruments regarding pain management and drug-induced side effects) on postoperative opioid patterns compared to standard preoperative care among patients undergoing elective surgery. Our end points were opioid consumption (number of pills used), appropriate disposal of unused opioids, opioid cessation (defined as no use of opioids), and opioid refills within 15 days, 6 weeks, and 3 months. Results In total, 11 RCTs fulfilled the inclusion criteria, totaling 1604 patients (804 received opioid education, while 800 received standard care). Six trials followed patients for 15 days after surgery, and 5 trials followed patients up to 3 months. After 15 days, the opioid education group consumed a lower number of opioid pills than those in the control group (weighted mean difference [WMD], -3.39 pills; 95% confidence interval [CI], -6.40 to -0.37; P =.03; I2 = 69%) with no significant difference in overall opioid cessation (odds ratio [OR], 0.25; 95% CI, 0.04-1.56; P = .14; I2 = 83%). Likewise, perioperative opioid education did not have significant effects on opioid cessation at 6 weeks (OR, 0.69; 95% CI, 0.45-1.05; P = .10; I2 = 0%) and 3 months (OR, 0.59; 95% CI,0.17-2.01; P = .10; I2 = 0%) after surgery, neither reduced the need for opioid refills at 15 days (OR, 0.57; 95% CI, 0.28-1.15; P = .12; I2 = 20%) and 6 weeks (OR, 1.08; 95% CI, 0.59-1.98; P = .80; I2 = 37%). There was no statistically significant difference in the rate of appropriate disposal of unused opioids between both groups (OR, 1.99; 95% CI, 0.66-6.00; P = .22; I2 = 71%). Subgroup analysis by type of educational intervention showed a statistical reduction of opioid consumption at 15 days when implementing multimedia/audiovisual strategies (4 trials: WMD, -4.05 pills; 95% CI, -6.59 to -1.50; P = .002; I2 = 45%), but there was no apparent decrease when using only paper-based strategies (2 trials: WMD, -2.31 pills; 95% CI, -12.21 to 7.59; P = .65; I2 = 80%). Conclusions Perioperative educational interventions reduced the number of opioid pills consumed at 15 days but did not demonstrate a significant effect on opioid cessation or opioid refills at 15 days, 6 weeks, and 3 months. Further randomized trials should focus on evidence-based educational interventions with strict homogeneity of material to draw a more definitive recommendation.

Background Inflammatory cytokines have been implicated in organ fibrosis; however, their role in the development of arthrofibrosis after total knee arthroplasty (TKA) has not been well explored. The purpose of this study is to assess whether perioperative synovial fluid or blood plasma cytokine levels are associated with reduced early post-TKA range of motion. Methods A total of 179 patients with end-stage idiopathic osteoarthritis undergoing TKA were enrolled in this prospective cohort study. Synovial fluid and blood plasma were collected prearthrotomy and plasma was collected longitudinally in the postacute care unit and on postoperative days (PODs) 1 and 2. Stiffness was defined as ≤95° range of motion measured with a goniometer at 6 weeks (±2 weeks). Results Thirty-two of 162 (19.8%) patients analyzed were stiff at 6 weeks postoperatively. Postoperative plasma levels of 9 cytokines (Eotaxin3, IL-5, IL12_23p40, IP10, VEGF, IL-7, IL-12p70, IL-16, IL-17a) were significantly different between stiff and nonstiff patients on POD1 and/or POD2. An association between preoperative plasma and synovial fluid cytokine levels and the development of postoperative stiffness was not detected. Conclusion The results of this study suggest that there is a distinct acute postoperative cytokine response profile in patients who develop stiffness 6 weeks after TKA. This profile was characterized by significant differences in levels of 9 cytokines over the first 2 postoperative days. These results identify cytokines that are potential biomarkers for risk of early stiffness after TKA and may play a role in the pathophysiology of this outcome.

Objectives Spinal cord ischemia secondary to trauma or a vascular occlusive event is a threatening phenomenon. The neuroprotective properties of minocycline have been shown in several models of central nervous system diseases and after spinal cord ischemia; however, the benefit of using the drug requires additional confirmation in different animal models. Astrocytes are essential as regulators of neuronal functions and for providing nutrients. The authors hypothesized that astrocytes in the spinal cord may be an important target for minocycline action after ischemia and thus in the prevention of secondary spreading damage. Design A prospective, randomized animal study. Setting University research laboratory, single institution. Participants Adult male Sprague Dawley rats, weighing between 400 and 450 g. Interventions A model of spinal cord ischemia in the rat was used for this study to determine whether a single, high-dose (10 mg/kg) of minocycline protects against damage to the neuronal cytoskeleton, both in the white and gray matter, and whether it reduces glial fibrillary acidic protein levels, which is an index for prevention of astrocyte activation during ischemia. Thirty minutes before thoracic aorta occlusion, minocycline was administered for 18 minutes using a 2 F Fogarty catheter. Measurements and Main Results Minocycline given prophylactically significantly mitigated severe hindlimb motor impairment and reduced glial fibrillary acidic protein plus astrocytosis in both the white and gray matter of the spinal cord, caudal to the occlusion. Neuronal histologic cytoarchitecture, which was severely and significantly compromised in control animals, was preserved in the minocycline-treated animals. Conclusions This study's data imply that minocycline may attenuate reactive astrocytosis in response to injury with better neurologic outcome in a model of spinal cord ischemia in rats. The data suggest that future use of minocycline, clinically, might be advantageous in surgeries with a potential risk for paraplegia due to spinal cord ischemia.

Peripheral nerve injury–induced mechanical allodynia is often accompanied by abnormalities in the higher cortical regions, yet the mechanisms underlying such maladaptive cortical plasticity remain unclear. Here, we show that in male mice, structural and functional changes in the primary somatosensory cortex (S1) caused by peripheral nerve injury require neuron-microglial signaling within the local circuit. Following peripheral nerve injury, microglia in the S1 maintain ramified morphology and normal density but up-regulate the mRNA expression of brain-derived neurotrophic factor (BDNF). Using in vivo two-photon imaging and Cx3cr1CreER;Bdnfflox mice, we show that conditional knockout of BDNF from microglia prevents nerve injury–induced synaptic remodeling and pyramidal neuron hyperactivity in the S1, as well as pain hypersensitivity in mice. Importantly, S1-targeted removal of microglial BDNF largely recapitulates the beneficial effects of systemic BDNF depletion on cortical plasticity and allodynia. Together, these findings reveal a pivotal role of cerebral microglial BDNF in somatosensory cortical plasticity and pain hypersensitivity., This study reveals that brain-derived neurotrophic factor (BDNF) from cerebral microglia contributes to nerve injury-induced synaptic remodeling and neuronal hyperactivity, and ultimately contributes to pain sensitivity in mice; removal of microglial BDNF has beneficial effects on cortical plasticity and pain.

BACKGROUND Spinal anesthesia is known to have numerous benefits, including reductions in nausea and opioid consumption; however, postdural puncture headache (PDPH) remains a significant risk associated with this technique. The literature specifically examining this complication in adolescents is scarce. Our primary objective was therefore (1) to estimate the incidence of PDPH with a 27G pencil-point needle in patients between the ages of 12 and 19 undergoing ambulatory lower extremity procedures and (2) to compare it to the incidence in adults aged 20-45 years. METHODS After institutional review board (IRB) approval, patients aged 12-45 years undergoing ambulatory lower extremity surgery were approached. Patients undergoing the procedure under combined spinal-epidural (CSE) or spinal anesthesia with a 27G pencil-point needle were eligible for enrollment. Patients were consented before surgery and received a survey via e-mail on postoperative day (POD) 4 inquiring about the presence of a headache. Each headache was described by the participant and assessed for severity, time of onset, duration, location, and whether it was of a postural nature. All patients reporting a postural headache were contacted by a physician author to confirm a diagnosis of PDPH using the International Headache Society diagnostic criteria. RESULTS A total of 656 patients were included in the analysis. Overall, 3.4% of patients developed PDPH. The percentage developing PDPH was 4.9% (3.0-7.8) among those aged 12-19 years and 1.8% (0.8-3.9) in the 20- to 45-year-old group. After adjusting for covariates, the age group between 12 and 19 years was associated with an almost 3-fold increase in the odds (2.8 [95% confidence interval {CI}, 1.1-7.3]) for the development of PDPH compared to that in the 20-45 age group. One patient in the adult group required an epidural blood patch. CONCLUSIONS The overall incidence for the development of PDPH in ambulatory patients

In DRG an increase in miR-133b-3p, miR-143-3p, and miR-1-3p correlates with the lack of development of neuropathic pain following a peripheral nerve injury. Using lentiviral (LV) vectors we found that a single injection of LV-miR-133b-3p or LV-miR-143-3p immediately after a peripheral nerve injury prevented the development of sustained mechanical and cold allodynia. Injection of LV-miR-133b-3p or LV-miR-143-3p by themselves or in combination, on day 3 post-injury produced a partial and transient reduction in mechanical allodynia and a sustained decrease in cold allodynia. Injection of LV-miR-1-3p has no effect. Co-injection of LV-miR-1a with miR-133b-3p or miR-143-3p on day 3 post-injury produced a sustained decrease in mechanical and cold allodynia. In DRG cultures, miR-133b-3p and miR-143-3p but not miR-1-3p, enhanced the depolarization-evoked cytoplasmic calcium increase. Using 3′UTR target clones containing a Gaussian luciferase reporter gene we found that with the 3′UTR-Scn2b, miR-133-3p and miR-143-3p reduced the expression while miR-1-3p enhanced the expression of the reporter gene. With the 3′UTR-TRPM8, miR-133-3p and miR-143-3p reduced the expression and miR-1-3p had no effect. With the 3′UTR-Piezo2, miR-133-3p increased the expression while miR-143-3p and miR-1-3p had no effect. LV-miR133b-3p, LV-miR-143-3p and LV-miR1a-3p reduced Scn2b-mRNA and Piezo2-mRNA. LV-miR133b-3p and LV-miR-143-3p reduced TRPM8-mRNA. LV-miR-133b-3p and LV-miR-143-3p prevent the development of chronic pain when injected immediately after the injury, but are only partially effective when injected at later times. LV-miR-1a-3p had no effect on pain, but complemented the actions of LV-miR-133b-3p or LV-miR-143-3p resulting in a sustained reversal of pain when co-injected 3 days following nerve injury.

Introduction: In 2014, New York (NY) became the 23rd state to legalize medical marijuana (MMJ). The purpose of this survey was to collect data about practicing NY physicians' comfort level, opinions, and experience in recommending or supporting patient use of MMJ. Materials and Methods: An anonymous web-based survey was distributed to medical societies and to academic departments in medical schools within NY. Results: A total of 164 responses were analyzed. Physician participants were primarily located in New York City and surrounding areas. The majority (71%) agreed that MMJ should be an option available to patients. Most respondents were not registered to certify MMJ in NY, but were willing to refer patients to registered physicians. Common reasons for not registering included specialty and federal status of cannabis. More than 75% reported having patients who used cannabis for symptom control, and 50% reported having patients who inquired about MMJ within the past year. Most respondents are willing to discuss MMJ with their patients, but had little familiarity with the state program and a modest knowledge of the endocannabinoid system. Pain was a common symptom for which cannabis was recommended by registered physicians (69%) and purportedly used by patients (83%). Most respondents would consider MMJ as an adjuvant to opioids, and 84% believed opioids have greater risks than MMJ. Conclusion: Given that the majority of surveyed physicians support MMJ as an option for patients, few are registered and have adequate knowledge of MMJ. Although our study sample is small and geographically limited, our survey results highlight key physician issues that are likely applicable to practitioners in other states. Concerted efforts are needed at the federal, state, and academic levels to provide practitioners with evidence-based guidelines for the safe use of MMJ.

Background AMPAkines augment the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the brain to increase excitatory outputs. These drugs are known to relieve persistent pain. However, their role in acute pain is unknown. Furthermore, a specific molecular and anatomic target for these novel analgesics remains elusive. Methods The authors studied the analgesic role of an AMPAkine, CX546, in a rat paw incision (PI) model of acute postoperative pain. The authors measured the effect of AMPAkines on sensory and depressive symptoms of pain using mechanical hypersensitivity and forced swim tests. The authors asked whether AMPA receptors in the nucleus accumbens (NAc), a key node in the brain’s reward and pain circuitry, can be a target for AMPAkine analgesia. Results Systemic administration of CX546 (n = 13), compared with control (n = 13), reduced mechanical hypersensitivity (50% withdrawal threshold of 6.05 ± 1.30 g [mean ± SEM] vs. 0.62 ± 0.13 g), and it reduced depressive features of pain by decreasing immobility on the forced swim test in PI-treated rats (89.0 ± 15.5 vs. 156.7 ± 18.5 s). Meanwhile, CX546 delivered locally into the NAc provided pain-relieving effects in both PI (50% withdrawal threshold of 6.81 ± 1.91 vs. 0.50 ± 0.03 g; control, n = 6; CX546, n = 8) and persistent postoperative pain (spared nerve injury) models (50% withdrawal threshold of 3.85 ± 1.23 vs. 0.45 ± 0.00 g; control, n = 7; CX546, n = 11). Blocking AMPA receptors in the NAc with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione inhibited these pain-relieving effects (50% withdrawal threshold of 7.18 ± 1.52 vs. 1.59 ± 0.66 g; n = 8 for PI groups; 10.70 ± 3.45 vs. 1.39 ± 0.88 g; n = 4 for spared nerve injury groups). Conclusions AMPAkines relieve postoperative pain by acting through AMPA receptors in the NAc.

Previous studies have shown that following peripheral nerve injury there was a downregulation of the gap junction protein connexin 36 (Cx36) in the spinal cord; however, it is not known whether Cx36 protein is expressed in the dorsal root ganglia (DRGs), nor if its levels are altered following peripheral nerve injuries. Here we address these aspects in the adult rat lumbar DRG. Cx36 mRNA was detected using qRT-PCR, and Cx36 protein was identified in DRG sections using immunohistochemistry (IHC) and immunofluorescence (IF). Double staining revealed that Cx36 co-localizes with both anti-β-III tubulin, a neuronal marker, and anti-glutamine synthetase, a satellite glial cell (SGC) marker. In neurons, Cx36 staining was mostly uniform in somata and fibers of all sizes and its intensity increased at the cell membranes. This labeling pattern was in contrast with Cx36 IF dots mainly found at junctional membranes in islet beta cells used as a control tissue. Co-staining with anti-Cx43 and anti-Cx36 showed that whereas mostly uniform staining of Cx36 was found throughout neurons and SGCs, Cx43 IF puncta were localized to SGCs. Cx36 mRNA was expressed in normal lumbar DRG, and it was significantly down-regulated in L4 DRG of rats that underwent sciatic nerve injury resulting in persistent hypersensitivity. Collectively, these findings demonstrated that neurons and SGCs express Cx36 protein in normal DRG, and suggested that perturbation of Cx36 levels may contribute to chronic neuropathic pain resulting from a peripheral nerve injury.

The spared nerve injury (SNI) model of neuropathic pain was first developed by Decosterd and Woolf in 2000 in Sprague Dawley rats to enhance reproducibility of injury and behavioral responses resulting from a partial nerve injury. Given the differences in methodology and inconsistent behavioral data published in the SNI model of neuropathic pain in mice, and given that interspecies behavioral comparisons using the same peripheral nerve injury are presently lacking, in this study we assessed the development of mechanical and cold allodynia for five weeks in C57BL/6 mice and Sprague Dawley rats that underwent SNI. In rats and mice, the tibial and peroneal branches were ligated then severed, leaving the sural branch intact. By controlling several factors in the surgical procedure and behavioral tests, we found that rats developed and maintained strong mechanical and robust cold allodynia immediately following the injury that was maintained for the duration of the experiment (five weeks). In comparison, mice developed mechanical allodynia to a lesser magnitude which peaked at 2 weeks, but did not develop cold allodynia. We found both temporal and qualitative differences in the development of allodynic behaviors between SNI-mice and SNI-rats. Parallel analysis of interspecies differences can be exploited to reveal novel molecular players leading to divergent pain behaviors.

Following injury, primary sensory neurons undergo changes that drive central sensitization and contribute to the maintenance of persistent hypersensitivity. NR2B expression in the dorsal root ganglia (DRG) has not been previously examined in neuropathic pain models. Here, we investigated if changes in NR2B expression within the DRG are associated with hypersensitivities that result from peripheral nerve injuries. This was done by comparing the NR2B expression in the DRG derived from two modalities of the spared nerve injury (SNI) model, since each variant produces different neuropathic pain phenotypes. Using the electronic von Frey to stimulate the spared and non-spared regions of the hindpaws, we demonstrated that sural-SNI animals develop sustained neuropathic pain in both regions while the tibial-SNI animals recover. NR2B expression was measured at Day 23 and Day 86 post-injury. At Day 23 and 86 post-injury, sural-SNI animals display strong hypersensitivity, whereas tibial-SNI animals display 50 and 100% recovery from post-injury-induced hypersensitivity, respectively. In tibial-SNI at Day 86, but not at Day 23 the perinuclear region of the neuronal somata displayed an increase in NR2B protein. This retention of NR2B protein within the perinuclear region, which will render them non-functional, correlates with the recovery observed in tibial-SNI. In sural-SNI at Day 86, DRG displayed an increase in NR2B mRNA which correlates with the development of sustained hypersensitivity in this model. The increase in NR2B mRNA was not associated with an increase in NR2B protein within the neuronal somata. The latter may result from a decrease in kinesin Kif17, since Kif17 mediates NR2B transport to the soma’s plasma membrane. In both SNIs, microglia/macrophages showed a transient increase in NR2B protein detected at Day 23 but not at Day 86, which correlates with the initial post-injury induced hypersensitivity in both SNIs. In tibial-SNI at Day 86, but not at Day 23, satellite glia cells (SGCs) displayed an increase in NR2B protein. This study is the first to characterize of cell-specific changes in NR2B expression within the DRG following peripheral nerve injury. We discuss how the observed NR2B changes in DRG can contribute to the different neuropathic pain phenotypes displayed by each SNI variant.

Background The function of the Cannabinoid 1 receptor (CB1R) in the development of neuropathic pain is not clear. Mounting evidence suggest that CB1R expression and activation may contribute to pain. Cannabinoid 1 receptor knockout mice (CB1R−/−) generated on a C57Bl/6 background exhibit hypoalgesia in the hotplate assay and formalin test. These findings suggest that Cannabinoid 1 receptor expression mediates the responses to at least some types of painful stimuli. By using this mouse line, we sought to determine if the lack of Cannabinoid 1 receptor unveils a general hypoalgesic phenotype, including protection against the development of neuropathic pain. The acetone test was used to measure cold sensitivity, the electronic von Frey was used to measure mechanical thresholds before and after spared-nerve injury, and analysis of footprint patterns was conducted to determine if motor function is differentially affected after nerve-injury in mice with varying levels of Cannabinoid 1 receptor. Results At baseline, CB1R−/− mice were hypersensitive in the acetone test, and this phenotype was maintained after spared-nerve injury. Using calcium imaging of lumbar dorsal root ganglion (DRG) cultures, a higher percentage of neurons isolated from CB1R−/− mice were menthol sensitive relative to DRG isolated from wild-type (CB1R+/+) mice. Baseline mechanical thresholds did not differ among genotypes, and mechanical hypersensitivity developed similarly in the first two weeks following spared-nerve injury (SNI). At two weeks post-SNI, CB1R−/− mice recovered significantly from mechanical hypersensitivity, while the CB1R+/+ mice did not. Heterozygous knockouts (CB1R+/−) transiently developed cold allodynia only after injury, but recovered mechanical thresholds to a similar extent as the CB1R−/− mice. Sciatic functional indices, which reflect overall nerve health, and alternation coefficients, which indicate uniformity of strides, were not significantly different among genotypes. Conclusion Cold allodynia and significant recovery from spared-nerve injury-induced mechanical hypersensitivity are two novel phenotypes which characterize the global CB1R−/− mice. An increase in transient receptor potential channel of melastatin 8 channel function in DRG neurons may underlie the cold phenotype. Recovery of mechanical thresholds in the CB1R knockouts was independent of motor function. These results indicate that CB1R expression contributes to the development of persistent mechanical hypersensitivity, protects against the development of robust cold allodynia but is not involved in motor impairment following spared-nerve injury in mice.

Nerve growth factor (NGF) plays a role in sympathetic neuron integrity and survival. Brain-derived neurotrophic factor (BDNF) also has trophic effects on sympathetic neurons. We report here the serendipitous finding that co-treatment of hippocampus with BDNF and the NGF antagonist TrkA-Fc leads to perivascular inflammation and marked vasoconstriction. This effect is not observed with either reagent alone or in combination with other control proteins. Because NGF supports sympathetic neuron health, we tested the hypothesis that BDNF combined with sympathetic compromise caused this effect. Superior cervical ganglia were removed bilaterally with concurrent BDNF infusion into hippocampus. Perivascular inflammation was observed at 3 days, but not 12 days post treatment, when sympathetic terminals had receded, suggesting that the presence of these terminals was necessary for inflammation. Since sympathetic dysfunction may lead to compensatory overactivity of norepinephrine (NE) signaling, we co-infused BDNF with NE in the hippocampus and observed perivascular inflammation. In humans, sympathetic overactivity has been reported in a variety of vascular diseases. Some of these diseases, e.g. primary Raynaud's, are not accompanied by serious inflammatory disease whereas others, such as scleroderma and systemic lupus, are. We speculate that BDNF may contribute to the transformation of sympathetic dysfunction to inflammatory disease.

The aims of this chapter are to: (1) examine the key developments leading up to the discovery the cannabinoid 1 receptor (CB1R) and (2) assess the potential therapeutic benefits of cannabinoid drugs with respect to neurogenesis in the adult brain and spinal cord. As one of the most abundant G-protein coupled receptors found in the central nervous system, localization of CB1R and its role in the mature and in the developing brain will be discussed. Pharmacological studies with cannabinergic drugs, and studies utilizing knock-out mice of various endocannabinoid system components will be reviewed in the context of adult brain neurogenesis. The apparent conflicting data reveal the complexity of endocannabinoid signaling in this process. Though many studies have focused on CB1R and neurogenesis in the brain, none have evaluated the potential ability for CB1R to modulate the fate, and specifically neuronal differentiation, of adult spinal cord progenitors. The implications for CB1R modulation of adult neurogenesis are pivotal for understanding the behavioral and cognitive effects of chronic marijuana use, but also for assessing the potential consequences of pharmacotherapeutics with CB1R agonists or antagonists

Spinal cord motor neuron cultures are an important tool for the study of mechanisms involved in motor neuron survival, degeneration and regeneration, volatile anesthetic-induced immobility, motor neuron disorders such as amyotrophic lateral sclerosis or spinal muscular atrophy as well as in spinal cord injury. Embryonic spinal cord motor neurons derived from rats have been successfully cultured; unfortunately, the culture of adult motor neurons has been problematic due to their short-term survival. Recently, by using a cocktail of target-derived factors, neurotrophins (brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor) and a permeable cyclic adenosine monophosphate analog, we have established a reproducible protocol for long-term cultures of healthy and functional adult motor neurons (Exp Neurol 220:303-315, 2009). Here, we now describe in detail the steps that we used for the optimization of the process of isolation and maintenance of adult rat ventral horn motor neurons in vitro.

Background: Infusion of exogenous vascular endothelial growth factor (VEGF) into adult brain at doses above 60 ng/day induces dramatic angiogenesis accompanied by vascular leak and inflammation. Blood vessels formed by this treatment are dilated and tortuous, exhibiting a pathological morphology. Pathological VEGF-induced angiogenesis is preceded by vascular leak and inflammation, which have been proposed to mediate subsequent angiogenesis. Methods: To test this hypothesis, we infused VEGF into the brains of adult rats to induce pathological angiogenesis. Some of these rats were treated with dexamethasone, a potent anti-inflammatory glucocorticoid, to inhibit inflammation and edema. Results: We demonstrate that inhibition of inflammation by treatment with dexamethasone significantly attenuated VEGF-induced pathological angiogenesis. To present converging evidence that inflammation may be important in this angiogenic process, we also demonstrate that mice genetically deficient in the inflammatory mediator intercellular adhesion molecule-1 have attenuated VEGF-induced angiogenesis. These same mice showed normal amounts of physiological angiogenesis in response to enriched environments, however, suggesting that a generalized reduction in vascular plasticity could not account for their poor angiogenic response to VEGF. Conclusions: Taken together, the data from these experiments suggest that the inflammation which occurs before or during VEGF-induced pathological brain angiogenesis plays a contributory role in the pathological angiogenic process.