Effect of Intravenous Alfentanil on Nonpainful Thermally Induced Hyperalgesia in Healthy Volunteers.

Experimental interventions that activate specific components of clinical pain are necessary for characterization of underlying mechanisms and pharmacology. Cutaneous hyperalgesia has been described that uses nonpainful heat to induce secondary hyperalgesia. This study evaluated the effect of intravenous alfentanil on experimental cutaneous hyperalgesia created using this method. Eighteen subjects participated in a randomized, double-blinded, placebo-controlled crossover study consisting of 2 sessions, 1 with alfentanil and 1 with placebo. Using a computer-controlled infusion pump, alfentanil or matching placebo was maintained at a constant plasma level of 75 ng/mL for 1 hour followed by the application of a 40°C heat stimulus to the right thenar eminence for 15 minutes. The temperature was raised by 1°C every 15 minutes until the subject reported pain or 45°C was reached. After the end point was reached, the temperature was maintained, and repeat testing was performed. The nonpainful heat created an area of secondary cutaneous hyperalgesia and significant decrease in mechanical pain threshold on heat-treated right vs untreated left during placebo administration. Alfentanil prevented the hypersensitivity when compared to placebo (P < .05) but failed to reduce the area of secondary hyperalgesia created by nonpainful heat when compared to placebo (P = .06). Neither alfentanil nor the heat lamp treatment showed any significant effect on other neurosensory measures. This study demonstrated a reliable production of cutaneous hyperalgesia using a nonpainful stimulus that is affected by the systemic delivery of alfentanil. This model for human cutaneous experimental pain may be a useful method for scientific characterization of analgesics.

Soliciting views of various communities on health research: a prelude to engagement in specific research projects.

BACKGROUND: Members of the public are increasingly engaged in health-service and biomedical research and provide input into the content of research, design and data sharing. As there is variation among different communities on how research is perceived, to engage all sectors of the general public research institutions need to customize their approach. OBJECTIVE: This paper explores how research institutions and community leaders can partner to determine the best ways to engage different sectors of the public in research. DESIGN: Following a literature review, a research institution engaged with four different sectors of the public through their respective representative community-based organizations (CBOs) by interviews with leaders, community member focus groups and a joint project. SETTING: San Diego and Imperial Counties, California, United States of America (USA). CONCLUSION: Before embarking on more specific research projects, investigators can gain valuable insights about different communities' attitudes to, and understanding of, health services and biomedical research by interacting directly with members of the community, collaborating with community leaders, and jointly identifying steps of engagement tailored to the community.

Extended access to nicotine leads to a CRF1 receptor dependent increase in anxiety-like behavior and hyperalgesia in rats.

Tobacco dependence is associated with the emergence of negative emotional states during withdrawal, including anxiety and nociceptive hypersensitivity. However, the current animal models of nicotine dependence have focused on the mechanisms that mediate the acute reinforcing effects of nicotine and failed to link increased anxiety and pain during abstinence with excessive nicotine self-administration. Here, we tested the hypothesis that the activation of corticotropin-releasing factor-1 (CRF1 ) receptors and emergence of the affective and motivational effects of nicotine abstinence only occur in rats with long access (>21 hours/day, LgA) and not short (1 hour/day, ShA) access to nicotine self-administration. ShA and LgA rats were tested for anxiety-like behavior, nociceptive thresholds, somatic signs of withdrawal and nicotine intake after 3 days of abstinence. The role of CRF1 receptors during abstinence was tested using systemic or intracerebral infusion of MPZP (N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo(1,5α)pyrimidin-7-amine), a CRF1 receptor antagonist, in the central nucleus of the amygdala (CeA). LgA but not ShA rats exhibited abstinence-induced increases in anxiety-like behavior and nociceptive hypersensitivity, which both predicted subsequent excessive nicotine intake and were prevented by systemic administration of MPZP. Intra-CeA MPZP infusion prevented abstinence-induced increases in nicotine intake and nociceptive hypersensitivity. These findings demonstrate that the model of short access to nicotine self-administration has limited validity for tobacco dependence, highlight the translational relevance of the model of extended-intermittent access to nicotine self-administration for tobacco dependence and demonstrate that activation of CRF1 receptors is required for the emergence of abstinence-induced anxiety-like behavior, hyperalgesia and excessive nicotine intake.

Chronic CRF1 receptor blockade reduces heroin intake escalation and dependence-induced hyperalgesia.

Opioids represent effective drugs for the relief of pain, yet chronic opioid use often leads to a state of increased sensitivity to pain that is exacerbated during withdrawal. A sensitization of pain-related negative affect has been hypothesized to closely interact with addiction mechanisms. Neuro-adaptive changes occur as a consequence of excessive opioid exposure, including a recruitment of corticotropin-releasing factor (CRF) and norepinephrine (NE) brain stress systems. To better understand the mechanisms underlying the transition to dependence, we determined the effects of functional antagonism within these two systems on hyperalgesia-like behavior during heroin withdrawal utilizing models of both acute and chronic dependence. We found that passive or self-administered heroin produced a significant mechanical hypersensitivity. During acute opioid dependence, systemic administration of the CRF1 receptor antagonist MPZP (20 mg/kg) alleviated withdrawal-induced mechanical hypersensitivity. In contrast, several functional adrenergic system antagonists (clonidine, prazosin, propranolol) failed to alter mechanical hypersensitivity in this state. We then determined the effects of chronic MPZP or clonidine treatment on extended access heroin self-administration and found that MPZP, but not clonidine, attenuated escalation of heroin intake, whereas both drugs alleviated chronic dependence-associated hyperalgesia. These findings suggest that an early potentiation of CRF signaling occurs following opioid exposure that begins to drive both opioid-induced hyperalgesia and eventually intake escalation.

Corticotropin-releasing factor (CRF) and α 2 adrenergic receptors mediate heroin withdrawal-potentiated startle in rats.

Anxiety is one of the early symptoms of opioid withdrawal and contributes to continued drug use and relapse. The acoustic startle response (ASR) is a component of anxiety that has been shown to increase during opioid withdrawal in both humans and animals. We investigated the role of corticotropin-releasing factor (CRF) and norepinephrine (NE), two key mediators of the brain stress system, on acute heroin withdrawal-potentiated ASR. Rats injected with heroin (2 mg/kg s.c.) displayed an increased ASR when tested 4 h after heroin treatment. A similar increase in ASR was found in rats 10-20 h into withdrawal from extended access (12 h) to i.v. heroin self-administration, a model that captures several aspects of heroin addiction in humans. Both the α 2 adrenergic receptor agonist clonidine (10 µg/kg s.c.) and CRF1 receptor antagonist N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5-a] pyrimidin-7-amine (MPZP; 20 mg/kg s.c.) blocked heroin withdrawal-potentiated startle. To investigate the relationship between CRF1 and α 2 adrenergic receptors in the potentiation of the ASR, we tested the effect of MPZP on yohimbine (1.25 mg/kg s.c.)-potentiated startle and clonidine on CRF (2 µg i.c.v.)-potentiated startle. Clonidine blocked CRF-potentiated startle, whereas MPZP partially attenuated but did not reverse yohimbine-potentiated startle, suggesting that CRF may drive NE release to potentiate startle. These results suggest that CRF1 and α 2 receptors play an important role in the heightened anxiety-like behaviour observed during acute withdrawal from heroin, possibly via CRF inducing the release of NE in stress-related brain regions.

The NK1 receptor antagonist L822429 reduces heroin reinforcement.

Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1 h: ShA) or long (12 h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward- and stress-related brain areas both in ShA and LgA rats compared with heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects.

A dysphoric-like state during early withdrawal from extended access to methamphetamine self-administration in rats.

RATIONALE: Negative emotional states during drug withdrawal may contribute to compulsive drug intake and seeking in humans. Studies suggest that extended access to methamphetamine induces compulsive drug intake in rats. OBJECTIVE: The present study tested the hypothesis that compulsive methamphetamine intake in rats with extended access is associated with negative emotional states during drug withdrawal. METHODS: Rats with short (1 h, ShA) and extended access (6 h, LgA) to methamphetamine self-administration (0.05 mg/kg/infusion) were tested for reward thresholds using intracranial self-stimulation (ICSS). Different groups of ShA and LgA rats were examined for depression-like and anxiety-like states in the novelty-suppressed feeding, open field, defensive burying, and forced swim tests. RESULTS: With extended access, ICSS thresholds gradually increased, which was correlated with the increase of drug intake. During drug withdrawal, the increased ICSS thresholds returned to levels observed before exposure to extended access to methamphetamine. Upon re-exposure to extended access to methamphetamine, ICSS thresholds showed a more rapid escalation than during the initial exposure. LgA rats showed a longer latency to approach chow in the center of a novel field and remained immobile longer in the forced swim test than ShA rats did during early withdrawal. In contrast, ShA rats actively buried an aversive shock probe whereas LgA rats remained immobile in the defensive burying test. CONCLUSION: The data suggest that extended access to methamphetamine produces a more depressive-like state than anxiety-like state in rats during early withdrawal.

An observational study of the influence of "white-coat hypertension" on day-of-surgery blood pressure determinations.

BACKGROUND: Because decisions as to what range of intraoperative blood pressure (BP) is consistent with cerebral well-being are often made in reference to "baseline BP," we sought to determine whether day-of-surgery BPs accurately reflect baseline BP, as defined by ambulatory clinic BPs over the preceding 7 months. METHODS: Consecutive patients (n=101) who were severely hypertensive (Severe-HTN), systolic (S)>160 mm Hg, or diastolic (D)>100 at first operating room BP (1st OR-BP) were identified retrospectively. Two additional groups were formed from patients whose 1st OR-BP was moderately hypertensive (Mod-HTN, systolic BP=140 to 159 and/or diastolic BP=90 to 99; and normotensive, SBP=110 to 139 and DBP<89). 1st OR-BP was compared with: (1) BP before transfer to the OR (Pre-OR-BP); (2) BP during ambulatory evaluation 1 to 30 days preoperatively (Preop-Eval-BP); and (3) Baseline-BP (average of at least 3 ambulatory clinic BPs during the preceding 7 months). Comorbidity data were collected. RESULTS: For Severe-HTNs, 1st OR-BP, and Pre-OR-BP (expressed as mean arterial pressure) exceeded Baseline-BP by 16.4±11.6 (SD) and 5.2±11.6 (SD), respectively (P<0.05). Preop-Eval-BP was not different from Baseline-BP. For Mod-HTNs, 1st OR-BP exceeded Baseline-BP by 7.4±8.1 (SD) (P<0.05). But, Pre-OR-BP and Preop-Eval-BP did not differ from Baseline-BP. Among normotensives, 1st OR-BP was not different from Preop-Eval-BP or Baseline-BP. Hypertension, number of antihypertensive medications, vascular diagnoses (peripheral, coronary, cerebral), diabetes, and renal disease were more common in the hypertensive groups. The number of antihypertensive medications, a history of coronary disease, and insulin administration were predictors of an increase in 1st OR-BP over Baseline-BP. CONCLUSIONS: For most patients whose 1st OR-BP is hypertensive, that BP is greater than ambulatory clinic BPs recorded during the preceding 7 months. For most patients with Severe-HTN at 1st OR-BP, day-of-surgery BPs overestimate Baseline-BP and reference to prehospitalization BPs is advisable. When 1st OR-BP is normotensive, that BP usually reflects Baseline-BP.

Cervical epidural depth: correlation between needle angle, cervical anatomy, and body surface area.

OBJECTIVES: Prior to performing a cervical interlaminar epidural steroid injection (CIESI), knowledge of the depth from lamina to epidural space may assist in preventing cord injury. METHODS: This is a prospective analysis of data including gender, age, weight, height, previous surgery, neck circumference, distances from tip of chin to sternal notch, occiput to C7 vertebral prominence, and ear lobe to tip of shoulder, pain score, angle from C7 vertebral prominence to the back, depth at which the Tuohy needle contacted T1 vertebral lamina and depth at which the epidural space was entered was conducted with 92 subjects, average age (± standard deviation [SD]) 41.3 ± 13.2 years underwent fluoroscopically guided C7-T1 intralaminar epidural steroid injections. RESULTS: Depth to lamina was the best individual predictor with an r value of 0.86. Weight, neck circumference, and body mass index (BMI) positively correlated with depth to epidural space with r values of 0.66, 0.62, and 0.61, respectively. A linear regression model of depth to lamina for predicting depth to epidural space was accurate to within ± 0.5 cm of the actual depth in 69% of subjects. However, when comparing predicted with actual depth to epidural space for individual subjects, the prediction was inaccurate by as much as 1.6 cm deep or 1.7 cm shallow. CONCLUSIONS: While statistically significant correlations do exist between both quantitative external body characteristics and depth to cervical epidural space and T1vertebral lamina to depth of cervical epidural space for fluoroscopically guided interlaminar epidural steroid injections at C7-T1, even the most optimal regression models do not permit clinical confidence in predicted depth to epidural space.

Chronic spinal compression model in minipigs: a systematic behavioral, qualitative, and quantitative neuropathological study.

The goal of the present study was to develop a porcine spinal cord injury (SCI) model, and to describe the neurological outcome and characterize the corresponding quantitative and qualitative histological changes at 4-9 months after injury. Adult Gottingen-Minnesota minipigs were anesthetized and placed in a spine immobilization frame. The exposed T12 spinal segment was compressed in a dorso-ventral direction using a 5-mm-diameter circular bar with a progressively increasing peak force (1.5, 2.0, or 2.5 kg) at a velocity of 3 cm/sec. During recovery, motor and sensory function were periodically monitored. After survival, the animals were perfusion fixed and the extent of local SCI was analyzed by (1) post-mortem MRI analysis of dissected spinal cords, (2) qualitative and quantitative analysis of axonal survival at the epicenter of injury, and (3) defining the presence of local inflammatory changes, astrocytosis, and schwannosis. Following 2.5-kg spinal cord compression the animals demonstrated a near complete loss of motor and sensory function with no recovery over the next 4-9 months. Those that underwent spinal cord compression with 2 kg force developed an incomplete injury with progressive partial neurological recovery characterized by a restricted ability to stand and walk. Animals injured with a spinal compression force of 1.5 kg showed near normal ambulation 10 days after injury. In fully paralyzed animals (2.5 kg), MRI analysis demonstrated a loss of spinal white matter integrity and extensive septal cavitations. A significant correlation between the magnitude of loss of small and medium-sized myelinated axons in the ventral funiculus and neurological deficits was identified. These data, demonstrating stable neurological deficits in severely injured animals, similarities of spinal pathology to humans, and relatively good post-injury tolerance of this strain of minipigs to spinal trauma, suggest that this model can successfully be used to study therapeutic interventions targeting both acute and chronic stages of SCI.

Development of mechanical hypersensitivity in rats during heroin and ethanol dependence: alleviation by CRF1 receptor antagonism.

Animal models of drug dependence have described both reductions in brain reward processes and potentiation of stress-like (or anti-reward) mechanisms, including a recruitment of corticotropin-releasing factor (CRF) signaling. Accordingly, chronic exposure to opiates often leads to the development of mechanical hypersensitivity. We measured paw withdrawal thresholds (PWTs) in male Wistar rats allowed limited (short access group: ShA) or extended (long access group: LgA) access to heroin or cocaine self-administration, or in rats made dependent on ethanol via ethanol vapor exposure (ethanol-dependent group). In heroin self-administering animals, after transition to LgA conditions, thresholds were reduced to around 50% of levels observed at baseline, and were also significantly lower than thresholds measured in animals remaining on the ShA schedule. In contrast, thresholds in animals self-administering cocaine under either ShA (1 h) or LgA (6 h) conditions were unaltered. Similar to heroin LgA rats, ethanol-dependent rats also developed mechanical hypersensitivity after eight weeks of ethanol vapor exposure compared to non-dependent animals. Systemic administration of the CRF1R antagonist MPZP significantly alleviated the hypersensitivity observed in rats dependent on heroin or ethanol. The emergence of mechanical hypersensitivity with heroin and ethanol dependence may thus represent one critical drug-associated negative emotional state driving dependence on these substances. These results also suggest a recruitment of CRF-regulated nociceptive pathways associated with escalation of intake and dependence. A greater understanding of relationships between chronic drug exposure and pain-related states may provide insight into mechanisms underlying the transition to drug addiction, as well as reveal new treatment opportunities. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

A vaccine strategy that induces protective immunity against heroin.

Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. A vaccine capable of blocking heroin's effects could provide a long-lasting and sustainable adjunct to heroin addiction therapy. Heroin, however, presents a particularly challenging immunotherapeutic target, as it is metabolized to multiple psychoactive molecules. To reconcile this dilemma, we examined the idea of a singular vaccine with the potential to display multiple drug-like antigens; thus two haptens were synthesized, one heroin-like and another morphine-like in chemical structure. A key feature in this approach is that immunopresentation with the heroin-like hapten is thought to be immunochemically dynamic such that multiple haptens are simultaneously presented to the immune system. We demonstrate the significance of this approach through the extremely rapid generation of robust polyclonal antibody titers with remarkable specificity. Importantly, both the antinociceptive effects of heroin and acquisition of heroin self-administration were blocked in rats vaccinated using the heroin-like hapten.

Effects of lidocaine patch on intradermal capsaicin-induced pain: a double-blind, controlled trial.

UNLABELLED: This study evaluated the effects of topical lidocaine on skin sensation and on intradermal capsaicin-induced pain and hyperalgesia. A randomized, double-blinded, placebo controlled methodology was used. After baseline sensory testing, a placebo patch and a lidocaine patch were randomized to the volar aspect of the left or right forearm for 4 hours. The right forearm patch was removed, the sensory testing was repeated, and capsaicin was injected intradermally at the site. Pain scores were measured at the time of injection and every 2.5 minutes for 10 minutes followed by measurement of the hyperalgesic area to von Frey hair and stroking, flare response, and repeat sensory testing. At the completion of the testing on the right forearm, the left forearm patch was removed and the procedures described for the right forearm were repeated for the left forearm. There was a significant reduction in cool sensation, warm sensation, and touch thresholds in the lidocaine but not placebo patch arm. The lidocaine patch had no significant effect on hot pain or mechanical pain thresholds. Intradermal capsaicin resulted in a significant decrease in hot pain and mechanical pain thresholds; however, lidocaine was unable to significantly reverse the thermal or mechanical hyperalgesia induced by capsaicin. The lidocaine patch did not reduce flare area, nor areas of hyperalgesia or allodynia. This study suggests that the sodium channels and the capsaicin receptors function independently to control peripheral terminal depolarization. PERSPECTIVE: The sodium channel and the transient receptor potential vanilloid 1 (TRPV1) receptor coexist on peripheral terminals of unmyelinated fibers. This study showed that activation of the TRPV1 receptor can depolarize the fibers in the presence of sodium channel blockade. This suggests that the sodium channel and TRPV1 receptor function independently in depolarizing the fibers.

Developing a vaccine against multiple psychoactive targets: a case study of heroin.

Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. Currently approved heroin addiction medications include drugs that bind at the same receptors (e.g. opioid receptors) occupied by heroin and/or its metabolites in the brain, but undesired side effects of these treatments, maintenance dependence and relapse to drug taking remains problematic. A vaccine capable of blocking heroin's effects could provide an economical, long-lasting and sustainable adjunct to heroin addiction therapy without the side effects associated with available treatment options. Heroin, however, presents a particularly challenging vaccine target as it is metabolized to multiple psychoactive molecules of differing lipophilicity, with differing abilities to cross the blood brain barrier. In this review, we discuss the opiate scaffolding and hapten design considerations to confer immunogenicity as well as the specificity of the immune response towards structurally similar opiates. In addition, we detail different strategies employed in the design of immunoconjugates for a vaccine-based therapy for heroin addiction treatment.

The role of interoception and alliesthesia in addiction.

This review presents a novel conceptualization of addiction, integrating the concepts of interoception (i.e., the CNS representation of visceral feelings) and alliesthesia (i.e., that rewarding properties of stimuli are dependent on the internal state of the individual) with existing theories. It is argued that the body state, as defined by the integration of interoceptive information, is a crucial arbiter of the risk for initiation of and transition to compulsive use of addictive compounds. Overall, individuals at risk for drug dependence are characterized by an altered internal bodily state that leads to a change in hedonic and incentive motivational properties of addictive drugs. Specifically, drug dependent individuals experience alliesthesia of interoceptive processing, leading to increased incentive motivational properties of the drug over time and thereby increasing the probability of subsequent use. This extension of previous theories of addiction to include interoception and alliesthesia is based upon a clearly delineated set of neural substrates mediating interoception, key elements of which also recently have been implicated in drug addiction. The model thereby provides new potential targets for interventions that are aimed at changing the internal state that puts the individual at risk for continued substance use.

Sentinel lymph node accumulation of Lymphoseek and Tc-99m-sulfur colloid using a "2-day" protocol.

Lymphoseek is a receptor-binding radiopharmaceutical specifically designed for sentinel lymph node (SLN) mapping. We conducted a clinical trial which measured the injection site clearance and sentinel lymph node accumulation after a single intradermal injection of Lymphoseek or unfiltered [(99m)Tc]sulfur colloid (TcSC) using a "2-day" protocol for SLN mapping of breast cancer. Eleven patients with breast cancer participated in this study. Five patients received an intradermal administration of 1.0 nmol of (99m)Tc-labeled Lymphoseek; SLN mapping was performed on four subjects within 19 to 27 h. Six subjects received an intradermal administration of TcSC; SLN mapping was performed on five subjects within 18 to 26 h. Lymphoseek exhibited a significantly (P<.001) faster injection site clearance than TcSC. The mean Lymphoseek clearance half-time was 2.18+/-1.09 h compared to 57.4+/-92.8 h for TcSC. The mean sentinel lymph node uptake of Lymphoseek (1.5+/-1.7%) and TcSC (3.5+/-3.1%) was statistically equivalent (P=.213). When an intradermal injection is employed, Lymphoseek demonstrated faster injection site clearance than unfiltered [(99m)Tc]sulfur colloid and persistent SLN accumulation for at least 24 h.

Relative potency of the opioid antagonists naloxone and 6-alpha-naloxol to precipitate withdrawal from acute morphine dependence varies with time post-antagonist.

The current study compared the potency of naloxone versus 6-alpha-naloxol to precipitate opioid withdrawal under varying conditions of morphine pretreatment history using suppression of operant responding for food reward as the index of withdrawal. Male Wistar rats trained to respond on a lever for food reward received pretreatment with either Vehicle (Morphine-Naïve), a single subcutaneous (SC) injection of 5.6 mg/kg morphine (Single Morphine), or two morphine injections at 24 h intervals (Repeat Morphine), with varying doses of naloxone or 6-alpha-naloxol injected SC 4 h post-morphine and 5 min prior to the 30 min test session. When responding over the entire 30 min operant session was examined, naloxone was only 5-fold more potent than 6-alpha-naloxol in suppressing operant responding under Morphine Naïve conditions, but this increased to a 65-fold potency difference after Single or Repeat Morphine pretreatment. Examination of the relative potency of these antagonists in the Early Phase of operant testing (5-15 min post-antagonist) revealed an even greater 100-fold potency difference between naloxone and 6-alpha-naloxol, but in the Late Phase of testing (25-35 min post-antagonist), this had declined to a 9-fold potency difference, comparable to the relative potency of naloxone to 6-alpha-naloxol under Morphine-Naïve conditions. The results confirm a differential potency of naloxone to its reduced conjugate 6-alpha-naloxol in vivo, and extend the observation of this phenomenon to an acute (single) pretreatment with a low dose of morphine and an additional sign of opioid withdrawal to those previously used. However, the results also indicate that delay in onset of action of 6-alpha-naloxol at opioid receptors in the central nervous system may contribute significantly to its reduced potency relative to naloxone under certain morphine pretreatment conditions.

Intermittent binge alcohol exposure during the periadolescent period induces spatial working memory deficits in young adult rats.

Human and animal studies suggest adolescence is a period of heightened sensitivity to adverse cognitive sequelae of alcohol exposure. The present study assessed the effects of intermittent binge ethanol intoxication during the periadolescent period of Wistar rats on subsequent performance in a Morris water maze spatial navigation task. On postnatal days 32-56, rats were exposed to ethanol or air 3 days/week via vapor inhalation chambers. Acquisition of spatial navigation was assessed beginning 5 days after the final day of exposure, with 3 days of training in the Morris Water maze (four trials per day spaced at 90-s intertrial intervals [ITIs]). Rats were placed into the water maze at one of four positions along the perimeter, with a different release position to begin each trial. A probe trial assessed retention of platform location on the day after the final set of training trials. Four days after this probe trial, rats entered a working memory phase in which the platform was in a new location each day and a variable ITI of 1, 2, or 4 h was inserted between Trials 1 and 2; Trials 3 and 4 followed at 90-s intervals after Trial 2 on each day. The "savings" in latency to find the platform and distance traveled before finding it from Trial 1 to Trial 2 on each day served as an index of working memory. Ethanol-exposed rats showed similar acquisition of spatial navigation as control rats during training, as well as similar retention of platform location during the probe trial. However, rats exposed to average blood alcohol level (BAL) >200 mg% showed accelerated forgetting, with decreased retention of platform location at the 2-h ITI (P < .05), compared to control rats. Therefore, a 4-week history of intermittent ethanol exposure at BAL in excess of 200 mg% during periadolescence led to a working memory deficit in young adult rats, demonstrated by accelerated forgetting of novel information. These behavioral data are consistent with findings from adolescent human studies, indicating that binge-style alcohol exposure during the periadolescent stage of development is associated with deficits in retention of information.

Effect of chronic oral gabapentin on capsaicin-induced pain and hyperalgesia: a double-blind, placebo-controlled, crossover study.

OBJECTIVES: There is an abundance of literature on the efficacy of gabapentin for the treatment of neuropathic pain. Two studies have demonstrated an effect of a single dose of gabapentin on experimental cutaneous hyperalgesia. This study evaluated the effect of chronic delivery of oral gabapentin on experimentally induced cutaneous hyperalgesia. METHODS: A randomized, double-blinded, placebo-controlled crossover design methodology was conducted. Participants took part in two 10-day study sessions, separated by a 7-day washout period. One session was with gabapentin and one with placebo. Study drug was administered 300 mg b.i.d. from day 1 to 3, 300 mg q.i.d. from day 4 to 6 and 600 mg t.i.d. from day 7 to 10. At baseline, day 4, day 7, and day 10, quantitative sensory testing was performed to thermal and mechanical stimuli. On day 10, only intradermal capsaicin was injected on the volar aspect of the forearm followed by an assessment of pain and hyperalgesia. Side effects were recorded by the participants each evening. RESULTS: Thirteen participants were enrolled into the study. Three dropped out because of intolerable side effects. Ten participants completed the study and were able to tolerate the highest dose of gabapentin. Oral gabapentin had no significant effect on acute sensory thresholds, pain, secondary hyperalgesia, or flare response induced by intradermal capsaicin. There were significantly more side effects associated with gabapentin with sedation and dizziness being the most common. DISCUSSION: This study demonstrated a lack of effect of the chronic delivery of oral gabapentin on experimentally induced cutaneous hyperalgesia. The discrepancy of this finding with other studies using single oral doses may be the result of differences in the models used and differences in drug kinetics and plasma levels. The results of this study do not correlate with the clinical studies on gabapentin, which demonstrate efficacy at 1800 mg/d.