The National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP).

For over 40 years, the National Institute of Neurological Disorders and Stroke/National Institutes of Health-funded Anticonvulsant Screening Program has provided a preclinical screening service for participants world-wide that helped identify/characterize new antiseizure compounds, a number of which advanced to the market for the treatment of epilepsy. The newly-renamed Epilepsy Therapy Screening Program (ETSP) has a refocused mission to identify novel agents which will help address the considerable remaining unmet medical needs in epilepsy. These include identifying antiseizure agents for treatment-resistant epilepsy, as well as anti-epileptogenic agents that will prevent the development of epilepsy or disease-modifying agents that will ameliorate or even cure established epilepsy and its comorbidities. This manuscript provides an overview of the ETSP's efforts aimed at identifying the next generation of therapeutic agents to further reduce the suffering from and burden of epilepsy.

Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP).

Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy. Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy. The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models. Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED50 164 mg/kg), mouse MES (ED50 83.5 mg/kg) and rat MES (ED50 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED50 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses. The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.

The newly developed CRF1-receptor antagonists, NGD 98-2 and NGD 9002, suppress acute stress-induced stimulation of colonic motor function and visceral hypersensitivity in rats.

Corticotropin releasing factor receptor 1 (CRF1) is the key receptor that mediates stress-related body responses. However to date there are no CRF1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats. CRF1 antagonists or vehicle were administered orogastrically (og) or subcutaneously (sc) before either intracerebroventricular (icv) or intraperitoneal (ip) injection of CRF (10 µg/kg), exposure to water avoidance stress (WAS, 60 min) or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval). Fecal pellet output (FPO), diarrhea and visceromotor responses were monitored. In vehicle (og)-pretreated rats, icv CRF stimulated FPO and induced diarrhea in >50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og) reduced the CRF-induced FPO response with an inhibitory IC50 of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67-87% and decreased WAS-induced-FPO by 23-53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg) inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF1 antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD.

Electrophysiological evidence for rapid 5-HT1A autoreceptor inhibition by vilazodone, a 5-HT1A receptor partial agonist and 5-HT reuptake inhibitor.

This study examined the effect of vilazodone, a combined serotonin (5-HT) reuptake inhibitor and 5-HT(1A) receptor partial agonist, paroxetine and fluoxetine on the sensitivity of 5-HT(1A) autoreceptors of serotonergic dorsal raphe nucleus neurons in rats. These effects were assessed by determining the intravenous dose of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) required to suppress the basal firing rate of these neurons by 50% (ID50) in anesthetized rats using in vivo electrophysiology. 5-HT uptake inhibition was determined by the ability of the compounds to reverse (±)-p-chloroamphetamine (PCA)-induced rat hypothalamic 5-HT depletion ex vivo. Acute vilazodone administration (0.63 and 2.1 µmol/kg, s.c.), compared with vehicle, significantly increased (2-3-fold) the ID50 of 8-OH-DPAT at 4 h, but not 24h after administration. Subchronic administration (3 days) significantly increased the ID50 value at 4 h (3-4-fold) and at 24 h (~2-fold). In contrast, paroxetine and fluoxetine at doses that were supramaximal for 5-HT uptake inhibition did not significantly alter the ID50 value of 8-OH-DPAT after acute or subchronic administration. Vilazodone antagonized the action of PCA 3.5 h and 5 h after a single dose (ID50 1.49 and 0.46 µmol/kg, s.c., respectively), but was inactive 18 h post-administration, corroborating the electrophysiological results at 24 h following acute administration. The results are consistent with the concept of rapid and, following repeated treatment, prolonged inhibition of 5-HT(1A) autoreceptors by vilazodone. This effect could occur by either direct interaction with, or desensitization of, these receptors, an effect which cannot be ascribed to vilazodone's 5-HT reuptake inhibiting properties.

The pharmacokinetics and pharmacodynamics of zaleplon delivered as a thermally generated aerosol in a single breath to volunteers.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of inhaled zaleplon were assessed in healthy volunteers. Forty participants received 0.5, 1, 2, or 4 mg zaleplon or placebo as a thermally generated aerosol in a randomized, double-blind, parallel-group, dose escalation study. Blood was collected up to 24 hours after dosing, and sedation was assessed up to 8 hours. Following inhalation, the observed median time to maximum plasma concentrations (25%, 75%) was 1.89 (1.45, 3.08) minutes and the mean (SD) elimination half-life was 1.24 (0.24) hours. The equilibration half-life for sedation (t(1/2) k(e0) ) was 1.16 (0.62, 2.17) minutes. The zaleplon AUC was dose proportional across doses, with a slope (90% confidence interval) of log-AUC versus log-dose of 0.92 (0.82, 1.02). No clinically significant changes were noted in laboratory values, vital signs, or spirometry. The most common adverse events were dizziness, somnolence, euphoria, headache, and visual disturbance. Zaleplon inhalation represents a safe, well-tolerated means of rapidly achieving effective plasma concentrations.

Targeting memory processes with drugs to prevent or cure PTSD.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder resulting from exposure to a severe traumatic stressor and an area of great unmet medical need. Advances in pharmacological treatments beyond the currently approved SSRIs are needed. AREAS COVERED: Background on PTSD, as well as the neurobiology of stress responding and fear conditioning, is provided. Clinical and preclinical data for investigational agents with diverse pharmacological mechanisms are summarized. EXPERT OPINION: Advances in the understanding of stress biology and mechanisms of fear conditioning plasticity provide a rationale for treatment approaches that may reduce hyperarousal and dysfunctional aversive memories in PTSD. One challenge is to determine if these components are independent or reflect a common underlying neurobiological alteration. Numerous agents reviewed have potential for reducing PTSD core symptoms or targeted symptoms in chronic PTSD. Promising early data support drug approaches that seek to disrupt dysfunctional aversive memories by interfering with consolidation soon after trauma exposure, or in chronic PTSD, by blocking reconsolidation and/or enhancing extinction. Challenges remain for achieving selectivity when attempting to alter aversive memories. Targeting the underlying traumatic memory with a combination of pharmacological therapies applied with appropriate chronicity, and in combination with psychotherapy, is expected to substantially improve PTSD treatment.

Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine.

OBJECTIVE: The present study evaluated inhaled loxapine for the acute treatment of agitation in patients with bipolar I disorder. METHODS: A Phase 3, randomized, double blind, placebo-controlled, parallel group inpatient study was performed at 17 psychiatric research facilities. Agitated patients (N=314) with bipolar I disorder (manic or mixed episodes) were randomized (1:1:1) to inhaled loxapine 5 mg or 10 mg, or inhaled placebo using the Staccato® system. Following baseline assessments, patients received Dose 1 and were evaluated for 24 hours. If required, up to two additional doses of study drug and/or lorazepam rescue medication were given. The primary efficacy endpoint was change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score two hours after Dose 1. The key secondary endpoint was the Clinical Global Impression-Improvement score at two hours after Dose 1. Additional endpoints included the changes from baseline in the PANSS-EC from 10 min through 24 hours after Dose 1. Safety was assessed by adverse events, vital signs, physical examinations, and laboratory tests. RESULTS: For the primary and key secondary endpoints, both doses of inhaled loxapine significantly reduced agitation compared with placebo. Reduced agitation, as reflected in PANSS-EC score, was evident 10 min after Dose 1 with both doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications (dysgeusia was reported in 17% of patients receiving active drug versus 6% receiving placebo). CONCLUSIONS: Inhaled loxapine provided a rapid, non-injection, well-tolerated acute treatment for agitation in patients with bipolar I disorder.

Discovery of N-(1-ethylpropyl)-[3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl]amine 59 (NGD 98-2): an orally active corticotropin releasing factor-1 (CRF-1) receptor antagonist.

The design, synthesis, and structure-activity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98-2), which required no chromatography. Compound 59 was characterized as an orally bioavailable, brain penetrant, and highly selective CRF-1 receptor antagonist. Occupancy of rat brain CRF-1 receptors was quantified using ex vivo receptor occupancy assays, using both brain tissue homogenates as well as brain slices receptor autoradiography. Behaviorally, oral administration of 59 significantly antagonized CRF-induced locomotor activity at doses as low as 10 mg/kg and dose-dependently reduced the restraint stress-induced ACTH increases.

Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine.

BACKGROUND: There is a need for a rapid-acting, non-injection, acute treatment for agitation. AIMS: To evaluate inhaled loxapine for acute treatment of agitation in schizophrenia. METHOD: This phase III, randomised, double-blind, placebo-controlled, parallel-group study (ClinicalTrials.gov number NCT00628589) enrolled 344 individuals who received one, two or three doses of inhaled loxapine (5 or 10 mg) or a placebo. Lorazepam rescue was permitted after dose two. The primary efficacy end-point was change from baseline in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) 2 h after dose one. The key secondary end-point was Clinical Global Impression-Improvement scale (CGI-I) score 2 h after dose one. RESULTS: Inhaled loxapine (5 and 10 mg) significantly reduced agitation compared with placebo as assessed by primary and key secondary end-points. Reduced PANSS-EC score was evident 10 min after dose one with both 5 and 10 mg doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications. CONCLUSIONS: Inhaled loxapine provided a rapid, well-tolerated acute treatment for agitation in people with schizophrenia.

Emergence of anti-conflict effects of zolpidem in rhesus monkeys following extended post-injection intervals.

RATIONALE: Zolpidem is a hypnotic drug that binds to γ-aminobutyric acid type A receptors but lacks consistently demonstrable anxiolytic efficacy. METHODS: Rhesus monkeys (N = 4) were trained under a multiple schedule in which food-maintained responding was programmed (18-response fixed ratio) for a 5-min period, followed by a 5-min period in which the food-maintained responding was suppressed by response-contingent electric shock (20-response fixed ratio). Doses of zolpidem (range = 0.03 to 1.0 mg/kg, i.v.) were administered 5 min before the session, and responding was re-assessed at three additional 20-min intervals. A similar experiment also was carried out with the non-selective benzodiazepine, triazolam, over a dose range of 0.001 to 0.1 mg/kg, i.v. RESULTS: Zolpidem did not engender a significant increase in average rates of suppressed responding at earlier time points; however, rates of non-suppressed responding were robustly decreased. At 45- and 65-min post-injection, zolpidem treatment resulted in a dose-dependent increase in rates of suppressed responding. In contrast, the non-selective benzodiazepine triazolam increased rates of suppressed responding in a dose-dependent manner at all four time points, although decreases in non-suppressed responding were less at the later time points. CONCLUSIONS: These findings suggest that zolpidem has anxiolytic-like effects, but only >25 min after i.v. injection in this rhesus monkey conflict model. It was hypothesized that time-dependent effects on the response rate-suppressing properties of zolpidem become tolerant (i.e., acute tolerance). Because anxiolytic-like effects remain stable throughout the session, the absence of rate-decreasing effects may "unmask" anti-conflict effects.

Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxiety, depression, and stress-related disorders: evidence from animal models.

Adaptive responding to threatening stressors is of fundamental importance for survival. Dysfunctional hyperactivation of corticotropin releasing factor type-1 (CRF(1)) receptors in stress response system pathways is linked to stress-related psychopathology and CRF(1) receptor antagonists (CRAs) have been proposed as novel therapeutic agents. CRA effects in diverse animal models of stress that detect anxiolytics and/or antidepressants are reviewed, with the goal of evaluating their potential therapeutic utility in depression, anxiety, and other stress-related disorders. CRAs have a distinct phenotype in animals that has similarities to, and differences from, those of classic antidepressants and anxiolytics. CRAs are generally behaviorally silent, indicating that CRF(1) receptors are normally in a state of low basal activation. CRAs reduce stressor-induced HPA axis activation by blocking pituitary and possibly brain CRF(1) receptors which may ameliorate chronic stress-induced pathology. In animal models sensitive to anxiolytics and/or antidepressants, CRAs are generally more active in those with high stress levels, conditions which may maximize CRF(1) receptor hyperactivation. Clinically, CRAs have demonstrated good tolerability and safety, but have thus far lacked compelling efficacy in major depressive disorder, generalized anxiety disorder, or irritable bowel syndrome. CRAs may be best suited for disorders in which stressors clearly contribute to the underlying pathology (e.g. posttraumatic stress disorder, early life trauma, withdrawal/abstinence from addictive substances), though much work is needed to explore these possibilities. An evolving literature exploring the genetic, developmental and environmental factors linking CRF(1) receptor dysfunction to stress-related psychopathology is discussed in the context of improving the translational value of current animal models.

The dopamine D(2) receptor partial agonist aplindore improves motor deficits in MPTP-treated common marmosets alone and combined with L-dopa.

Dopamine replacement therapy in Parkinson's disease (PD) using L-dopa is invariably associated with a loss of drug efficacy ("wearing off") and the onset of dyskinesia. The use of dopamine receptor partial agonists might improve therapeutic benefit without increased dyskinesia expression but may antagonise the effects of L-dopa. We now examine the effects of the novel high affinity, dopamine D(2) receptor partial agonist, aplindore alone and in combination with L-dopa in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. In non-dyskinetic MPTP treated animals, aplindore (0.05-1.0 mg/kg p.o.) produced a dose-dependent reversal of motor disability and an increase in locomotor activity that was maximal at doses of 0.2 mg/kg and above. In animals previously exposed to L: -dopa to induce dyskinesia, escalating and repeated dosing of aplindore (0.05-0.5 mg/kg p.o.) produced a sustained, dose-related improvement in motor disability and an increase in locomotor activity. The effects were maximal at a dose of 0.1 mg/kg and above and not different from those produced by L-dopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o.). Aplindore administration also led to dose-dependent expression of dyskinesia but at 0.1 mg/kg, this was significantly less intense than that produced by L-dopa. Administration of aplindore (1.0 mg/kg p.o.) in combination with L-dopa (2.5 mg/kg plus carbidopa 12.5 mg/kg p.o.) did not inhibit the reversal of motor deficits but improved motor disability and increased both locomotor activity and dyskinesia expression equivalent to that produced by L-dopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o.). These data suggest that dopamine receptor partial agonists would be effective in the treatment of Parkinson's disease and would not inhibit the beneficial actions of L-dopa.

Retrograde effects of triazolam and zolpidem on sleep-dependent motor learning in humans.

Drugs that act as allosteric activators at the benzodiazepine site of the gamma-aminobutyric acid (GABA(A)) receptor complex are used commonly to treat insomnia but relatively little is known of how such use affects learning and memory. Although anterograde effects on memory acquisition have been shown, possible retrograde effects on consolidation are more relevant when such agents are administered at bedtime. We tested the effects of two GABA(A) allosteric activators on sleep-dependent motor skill memory consolidation in 12 healthy male subjects. Subjects slept in a sleep laboratory for four consecutive nights (one accommodation night followed by three experimental nights). Placebo, triazolam 0.375 mg, and zolpidem 10 mg were given to each subject in counterbalanced order on the experimental nights. Polysomnographic (PSG) sleep measurement and sleep-dependent motor learning were assessed at each condition. Triazolam was associated with longer total sleep time and increased Stage 2 sleep. Both zolpidem and triazolam were associated with increased latency to rapid eye movement (REM) sleep. Overnight motor learning correlated with total sleep time in the placebo condition but not in the triazolam or zolpidem conditions. A statistically significant impairment in motor performance occurred overnight in the triazolam condition only. Triazolam, given in sufficient doses to prolong sleep in healthy people, affected overnight motor learning adversely. Zolpidem, in a dose sufficient to prolong REM onset latency but without other effects on PSG-measured sleep, degraded the relationship between total sleep time and overnight motor learning. These data indicate that non-selective or alpha1-preferring benzodiazepine site allosteric activators can interfere with sleep-dependent memory consolidation.

2-Arylpyrimidines: novel CRF-1 receptor antagonists.

The design, synthesis and structure-activity relationship studies of a novel series of CRF-1 receptor antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and the pyrimidine core on CRF-1 receptor binding were investigated. A number of compounds with K(i) values below 10 nM and lipophilicity in a minimally acceptable range for a CNS drug (cLogP<5) were discovered.

D2 receptor partial agonists: treatment of CNS disorders of dopamine function.

A remarkable diversity of psychiatric and neurological disorders have been associated with dysfunction of dopamine (DA)-containing neurons, including schizophrenia, bipolar disorder (BD), Parkinson's disease (PD), and restless legs syndrome (RLS). In such disorders, transmission in discrete DA pathways may range from hypoactivation to hyperactivation of DA receptors, particularly those of the D(2) subtype, providing the rationale for treatment approaches that activate or block D(2) receptors, respectively. However, full agonists or pure D(2) receptor antagonists may not be optimal therapeutic approaches for their respective disorders for a number of reasons, including an inability to restore the aberrant DA pathways to a normal level of basal tone. D(2) receptor partial agonists (D(2)PAs) are proposed to stabilize activity in DA pathways by dampening excessive (and/or by restoring deficient) D(2) receptor stimulation thereby shepherding DA neurons back to a desired level of basal activity. Stabilizing aberrant DA activity without disrupting non-dysfunctional DA neurons may provide a potentially improved approach for treating DA disorders. The status of DA D(2)PAs and their potential application to schizophrenia, BD, PD, and RLS is reviewed. Preclinical and clinical evidence supports the idea that dysfunctions of D(2) receptors contribute to these CNS disorders. Diseases in which both hyper- and hypofunction of DA pathways are present may be particularly promising, and challenging, targets for D(2)PAs. Furthermore, different DA disorders may respond optimally to D(2)PAs with differing levels of intrinsic activity, with "DA deficiency" diseases responding more effectively to higher intrinsic activity D(2)PAs than "DA hyperactivation" diseases. Overall, current evidence supports the conclusion that D(2)PAs have significant potential as improved CNS therapies relative to classic full agonists and antagonists at D(2) receptors.

The design, synthesis and structure-activity relationships of 1-aryl-4-aminoalkylisoquinolines: a novel series of CRF-1 receptor antagonists.

The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on CRF-1 receptor binding were investigated.

The CRF1 receptor, a novel target for the treatment of depression, anxiety, and stress-related disorders.

The present review focuses on the corticotropin releasing factor type 1 (CRF(1)) receptor as a novel target for treating depression, anxiety and other stress-related disorders. An organism's stress response system is a complex network of neuronal, endocrine and autonomic pathways which has evolved to provide adaptive reactions to severe environmental and physiological stressors. The peptide CRF plays a critical role in the proper functioning of the stress response system through its actions on CRF(1) receptors located at multiple anatomical sites. Clinical data indicate that dysfunctions of the stress response system, expressed as excessive CRF activity and possible hyperstimulation of CRF(1) receptors, are present in a range of stress-related disorders, including depression, anxiety, and irritable bowel syndrome. CRF(1) dysfunction may be particularly prominent in severe forms of these disorders (e.g. melancholic or psychotic depression, comorbid conditions, chronic posttraumatic stress disorder) and/or when these disorders are accompanied by a history of exposure to early life trauma. Available clinical data support the potential therapeutic efficacy of pharmacological agents which block the CRF(1) receptor. Preclinical studies demonstrate that CRF(1) receptor antagonists are efficacious in animal models in which CRF pathways and CRF(1) receptors are hyperactivated, whereas they tend to be quiescent in states of low basal CRF activity, indicative of potentially reduced side effects in humans. Symptom diversity in animal models of stress and in human stress disorders may result from dysfunctions in different CRF(1) receptor populations and/or different functional states of the CRF(1) receptor. Small molecule, orally-active CRF(1) receptor antagonists may be a broadly useful approach for treating a range of stress-related disorders that are associated with excessive CRF(1) receptor stimulation.

Inflammation-induced reduction of spontaneous activity by adjuvant: A novel model to study the effect of analgesics in rats.

The majority of rodent models used to evaluate analgesic drug effects rely on evoked measures of nociceptive thresholds as primary outcomes. These approaches are often time-consuming, requiring extensive habituation sessions and repeated presentations of eliciting stimuli, and are prone to false-positive outcomes due to sedation or tester subjectivity. Here, we describe the reduction of spontaneous activity by adjuvant (RSAA) model as an objective and quantifiable behavioral model of inflammatory pain that can predict the analgesic activity of a variety of agents following single-dose administration. In the RSAA model, activity was measured in nonhabituated rats using standard, photocell-based monitors. Bilateral inflammation of the knee joints by complete Freund's adjuvant (CFA) reduced the normal level of activity (horizontal locomotion and vertical rearing) by approximately 60% in a novel environment. This reduction in activity was dose-dependently reversed by ibuprofen, rofecoxib, celecoxib, piroxicam, and dexamethasone, whereas gabapentin and amitriptyline were inactive. Morphine significantly reversed the activity-suppressing effects of CFA, at 1 mg/kg s.c., but at higher doses locomotor activity progressively declined, coincident with the induction of sedation. In contrast to morphine and anti-inflammatory therapies, amphetamine did not affect vertical rearing, even though it increased horizontal locomotion. Thus, unlike standard measures of analgesia such as alteration in thermal or mechanical sensitivity, the RSAA model operationally defines analgesia as a drug-induced increase in spontaneous behavior (vertical rearing in a novel environment). We conclude that the RSAA model is valuable as an objective measure of analgesic efficacy that is not dependent on an evoked stimulus response.