Prevalence of Underreported Nicotine Exposure Among US Nonsmoking Adults: A Comparison of Self-Reported Exposure and Serum Cotinine Levels From NHANES 2013-2020.

INTRODUCTION: Secondhand smoke (SHS) poses a significant health risk. However, individuals who do not smoke may be unaware of their exposure, thereby failing to take protective actions promptly. AIMS AND METHODS: We assessed the prevalence of underreported nicotine exposure in a nationally representative sample of US nonsmoking adults using data from the US National Health and Examination Survey. Individuals with underreported nicotine exposure were defined as those who reported no exposure to all tobacco products (traditional tobacco, nicotine replacements, and e-cigarettes) or SHS, yet had detectable levels of serum cotinine (>0.015 ng/mL). We fitted logistic regression models to determine sociodemographic and chronic condition factors associated with underreported nicotine exposure. RESULTS: Our analysis included 13 503 adults aged 18 years and older. Between 2013 and 2020, the prevalence of self-reported SHS exposure, serum cotinine-assessed nicotine exposure, and underreported nicotine exposure among US nonsmokers were 22.0%, 51.2%, and 34.6%, respectively. Remarkably, 67.6% with detectable serum cotinine reported no SHS exposure. Males, non-Hispanic blacks, individuals of other races (including Asian Americans, Native Americans, and Pacific Islanders), and those without cardiovascular diseases were more likely to underreport nicotine exposure than their counterparts. The median serum cotinine value was higher in respondents who reported SHS exposure (0.107 ng/mL) than in those who reported no exposure (0.035 ng/mL). We estimate that approximately 56 million US residents had underreported nicotine exposure. CONCLUSIONS: Over a third of US nonsmokers underreport their nicotine exposure, underlining the urgent need for comprehensive public awareness campaigns and interventions. Further research into sociodemographic determinants influencing this underreporting is needed. IMPLICATIONS: Understanding the extent of underreported nicotine exposure is crucial for developing effective public health strategies and interventions. It is imperative to bolster public consciousness about the risks associated with SHS. Additionally, surveillance tools should also incorporate measures of exposure to outdoor SHS and e-cigarette vapor to enhance the quality of data monitoring. Findings from this study can guide tobacco control initiatives and inform smoke-free air legislation.

Development of Dependence in Smokers and Rodents With Voluntary Nicotine Intake: Similarities and Differences.

INTRODUCTION: Smoking and vaping throughout adolescence and early adulthood lead to nicotine dependence. Nicotine withdrawal is associated with somatic and affective withdrawal symptoms that contribute to smoking and relapse. Affective nicotine withdrawal symptoms in humans include craving for cigarettes, depression, anxiety, trouble sleeping, and cognitive deficits. METHODS: Herein, we review clinical studies that investigated nicotine dependence in people who smoke or vape. We also discuss studies that investigated the development of dependence in animals with oral nicotine intake, nicotine aerosol self-administration, and intravenous nicotine self-administration. RESULTS: Clinical studies report that adolescents who smoke daily develop nicotine dependence before those who smoke infrequently, but ultimately all smokers become dependent in adulthood. Preclinical studies indicate that rats that self-administer nicotine also become dependent. Rats that self-administer nicotine display somatic withdrawal signs and affective withdrawal signs, including increased anxiety and depressive-like behavior, cognitive deficits, and allodynia. Most nicotine withdrawal signs were observed in rodents with daily (7 days/week) or intermittent long access (23-hour) to nicotine. Clinical smoking studies report symptoms of nicotine dependence in adolescents of both sexes, but virtually all preclinical nicotine self-administration studies have been done with adult male rats. CONCLUSIONS: The role of sex and age in the development of dependence in nicotine self-administration studies remains under-investigated. However, the role of sex and age in nicotine withdrawal has been thoroughly evaluated in studies in which nicotine was administered noncontingently. We discuss the need for volitional nicotine self-administration studies that explore the gradual development of dependence during adolescence and adulthood in rodents of both sexes. IMPLICATIONS: The reviewed clinical studies investigated the development of nicotine dependence in male and female adolescent and young adult smokers and vapers. These studies indicate that most adolescent smokers and vapers gradually become nicotine dependent. Preclinical studies with rodents show that nicotine intake in widely used self-administration models also leads to dependence. However, almost all animal studies that investigated the development of nicotine dependence have been conducted with adult male rats. To better model smoking and vaping, it is important that nicotine intake in rats or mice starts during adolescence and that both sexes are included.

Dopamine D1-like receptor activation decreases nicotine intake in rats with short or long access to nicotine.

The use of nicotine and tobacco products is highly addictive. The dopaminergic system plays a key role in the initiation and maintenance of nicotine intake. Dopamine D1-like receptor blockade diminishes nicotine intake in rats with daily short (1 h) access to nicotine, but little is known about the effects of dopamine receptor antagonists or agonists on nicotine intake in rats with intermittent long (23 h) access. Because of the extended access conditions and high nicotine intake, the intermittent long access procedure might model smoking and vaping better than short access models. We investigated the effects of the dopamine D1-like receptor antagonist SCH 23390 and the D1-like receptor agonist A77636 on nicotine intake in male rats with intermittent short or long access to nicotine. The rats self-administered nicotine for 5 days (1 h/day) and were then given 15 intermittent short (1 h/day) or long (23 h/day) access sessions (3 sessions/week, 0.06 mg/kg/inf). The D1-like receptor antagonist SCH 23390 decreased nicotine intake to a similar degree in rats with short or long access to nicotine. The D1-like receptor agonist A77636 induced a greater decrease in nicotine intake in the rats with long access to nicotine than in rats with short access. Treatment with A77636 induced a prolonged decrease in nicotine intake that lasted throughout the dark and light phase in the long access rats. These findings indicate that blockade and stimulation of D1-like receptors decrease nicotine intake in an intermittent long access animal model that closely models human smoking and vaping.

Opportunities and Challenges of Kava in Lung Cancer Prevention.

Lung cancer is the leading cause of cancer-related deaths due to its high incidence, late diagnosis, and limited success in clinical treatment. Prevention therefore is critical to help improve lung cancer management. Although tobacco control and tobacco cessation are effective strategies for lung cancer prevention, the numbers of current and former smokers in the USA and globally are not expected to decrease significantly in the near future. Chemoprevention and interception are needed to help high-risk individuals reduce their lung cancer risk or delay lung cancer development. This article will review the epidemiological data, pre-clinical animal data, and limited clinical data that support the potential of kava in reducing human lung cancer risk via its holistic polypharmacological effects. To facilitate its future clinical translation, advanced knowledge is needed with respect to its mechanisms of action and the development of mechanism-based non-invasive biomarkers in addition to safety and efficacy in more clinically relevant animal models.

Oxycodone decreases anxiety-like behavior in the elevated plus-maze test in male and female rats.

The prescription opioid oxycodone is widely used for the treatment of pain in humans. Oxycodone misuse is more common among people with an anxiety disorder than those without one. Therefore, oxycodone might be misused for its anxiolytic properties. We investigated if oxycodone affects anxiety-like behavior in adult male and female rats. The rats were treated with oxycodone (0.178, 0.32, 0.56, or 1 mg/kg), and anxiety-like behavior was investigated in the elevated plus-maze test. Immediately after the elevated plus-maze test, a small open field test was conducted to determine the effects of oxycodone on locomotor activity. In the elevated plus-maze test, oxycodone increased the percentage of time spent on the open arms, the percentage of open arm entries, time on the open arms, open arm entries, and the distance traveled. The males treated with vehicle had a lower percentage of open arm entries than the females treated with vehicle, and oxycodone treatment led to a greater increase in the percentage of open arm entries in the males than females. Furthermore, the females spent more time on the open arms, made more open arm entries, spent less time in the closed arms, and traveled a greater distance than the males. In the small open field test, treatment with oxycodone did not affect locomotor activity or rearing. Sex differences were observed; the females traveled a greater distance and displayed more rearing than the males. In conclusion, oxycodone decreases anxiety-like behavior in rats, and oxycodone has a greater anxiolytic-like effect in males than females.

Rewarding Effects of Nicotine Self-administration Increase Over Time in Male and Female Rats.

INTRODUCTION: Smoking and the use of other nicotine-containing products is rewarding in humans. The self-administration of nicotine is also rewarding in male rats. However, it is unknown if there are sex differences in the reward-enhancing effects of nicotine self-administration and if the rewarding effects of nicotine change over time. METHODS: Rats were prepared with catheters and intracranial self-stimulation (ICSS) electrodes to investigate the effects of nicotine and saline self-administration on reward function. A decrease in thresholds in the ICSS procedure reflects an enhancement of reward function. The ICSS parameters were determined before and after the self-administration sessions from days 1 to 10, and after the self-administration sessions from days 11 to 15. RESULTS: During the first 10 days, there was no sex difference in nicotine intake, but during the last 5 days, the females took more nicotine than the males. During the first 10 days, nicotine self-administration did not lower the brain reward thresholds but decreased the response latencies. During the last 5 days, nicotine lowered the reward thresholds and decreased the response latencies. An analysis with the 5-day averages (days 1-5, 6-10, and 11-15) showed that the reward enhancing and stimulatory effects of nicotine increased over time. There were no sex differences in the reward-enhancing and stimulatory effects of nicotine. The nicotinic receptor antagonist mecamylamine diminished the reward-enhancing and stimulatory effects of nicotine. CONCLUSION: These findings indicate that the rewarding effects of nicotine self-administration increase over time, and there are no sex differences in the reward-enhancing effects of nicotine self-administration in rats. IMPLICATIONS: This study investigated the rewarding effect of nicotine and saline self-administration in male and female rats. The self-administration of nicotine, but not saline, enhanced brain reward function and had stimulatory effects. The rewarding effects of nicotine increased over time in the males and the females. Despite that the females had a higher level of nicotine intake than the males, the reward-enhancing effects of nicotine self-administration were the same. These findings suggest that in new tobacco and e-cigarette users, nicotine's rewarding effects might increase quickly, and a higher level of nicotine use in females might not translate into greater rewarding effects.

Rewarding Effects of Nicotine in Adolescent and Adult Male and Female Rats as Measured Using Intracranial Self-stimulation.

INTRODUCTION: Tobacco is highly addictive, and after the development of dependence, it is difficult to quit smoking. Therefore, it is important to understand the factors that play a role in the initiation of smoking. The rewarding effects of nicotine play a role in the initiation of smoking and the goal of the present study was to determine the rewarding effects of nicotine in adolescent and adult male and female rats. METHODS: Male and female Wistar rats were prepared with intracranial self-stimulation (ICSS) electrodes between postnatal day (P) 23 and 33. They were then trained on the ICSS procedure and the effect of nicotine (0, 0.03, 0.1, 0.3 mg/kg) on the reward thresholds and response latencies was investigated during adolescence (P40-59) or adulthood (>P75). RESULTS: Nicotine lowered the brain reward thresholds of the adult and adolescent male and female rats. The nicotine-induced decrease in the reward thresholds was the same in the adult male and adult female rats. However, nicotine induced a greater decrease in the reward thresholds of the adolescent female rats than the adolescent male rats. Nicotine decreased the response latencies of all groups and there was no effect of age or sex. CONCLUSIONS: Nicotine enhances reward function and psychomotor performance in adolescent and adult male and female rats. Adolescent female rats are more sensitive to the acute rewarding effects of nicotine than adolescent male rats. Therefore, the rewarding effects of nicotine might play a greater role in the initiation of smoking in adolescent females than in adolescent males. IMPLICATIONS: The great majority of people start smoking during adolescence. The present studies suggest that during this period female rats are more sensitive to the acute rewarding effects of low and intermediate doses of nicotine than male rats. The rewarding properties of nicotine play a role in the initiation of smoking and establishing habitual smoking. Therefore, the present findings might explain why adolescent females are at a higher risk for becoming nicotine dependent than adolescent males.

Evaluation of Sex Differences in the Elasticity of Demand for Nicotine and Food in Rats.

INTRODUCTION: Animal studies can inform policy regarding nicotine levels in tobacco products and e-cigarette solutions. Increasing the price of nicotine-containing products decreases their use, but it is unknown how the relationship between price and consumption is affected by both sex and nicotine dose. METHODS: A behavioral economics procedure was used to determine the demand elasticity for nicotine in male and female rats. Demand elasticity describes the relationship between price and consumption. A high level of elasticity indicates that consumption is relatively sensitive to increases in price. The rats self-administered a low dose (0.01 mg/kg/inf) or a standard dose (0.03 mg/kg/inf) of nicotine for 9 days under a fixed-ratio (FR) 1 schedule. Then the price (FR schedule) of nicotine was increased, and a demand analysis was conducted. A similar study was conducted with palatable food pellets. RESULTS: There were no sex differences in nicotine or food intake under the FR1 schedule. However, demand for 0.03 mg/kg/inf of nicotine was more elastic in females than males. Demand for 0.01 mg/kg/inf of nicotine and food was more elastic in males than females. CONCLUSIONS: These findings indicate that there are no differences in nicotine and food intake between males and females when the price is low. When the price of nicotine or food is increased, males maintain their old level of intake longer than females when they have access to a standard dose of nicotine, and females maintain their intake longer when they have access to a low dose of nicotine or food. IMPLICATIONS: This behavioral economics analysis indicates that there is no sex difference in nicotine intake when the price of nicotine is low. Increasing the price of nicotine decreases nicotine intake in a dose- and sex-specific manner. Males maintain their old level of intake longer when they have access to a standard dose of nicotine and females when they have access to a low dose. This has implications for tobacco regulatory policy. In a regulatory environment where only low nicotine-containing products are allowed, increasing the price of nicotine products may lead to a greater decrease in nicotine use in males than females.

Relationship Between Nicotine Intake and Reward Function in Rats With Intermittent Short Versus Long Access to Nicotine.

INTRODUCTION: Tobacco use improves mood states and smoking cessation leads to anhedonia, which contributes to relapse. Animal studies have shown that noncontingent nicotine administration enhances brain reward function and leads to dependence. However, little is known about the effects of nicotine self-administration on the state of the reward system. METHODS: To investigate the relationship between nicotine self-administration and reward function, rats were prepared with intracranial self-stimulation electrodes and intravenous catheters. The rats were trained on the intracranial self-stimulation procedure and allowed to self-administer 0.03 mg/kg/infusion of nicotine. All rats self-administered nicotine daily for 10 days (1 hour/day) and were then switched to an intermittent short access (ShA, 1 hour/day) or long access (LgA, 23 hour/day) schedule (2 days/week, 5 weeks). RESULTS: During the first 10 daily, 1-hour sessions, nicotine self-administration decreased the reward thresholds, which indicates that nicotine potentiates reward function. After switching to the intermittent LgA or ShA schedule, nicotine intake was lower in the ShA rats than the LgA rats. The LgA rats increased their nicotine intake over time and they gradually consumed a higher percentage of their nicotine during the light phase. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine induced a larger increase in reward thresholds (ie, anhedonia) in the LgA rats than the ShA rats. In the LgA rats, nAChR blockade with mecamylamine decreased nicotine intake for 2 hours and this was followed by a rebound increase in nicotine intake. CONCLUSIONS: A brief period of nicotine self-administration enhances reward function and a high level of nicotine intake leads to dependence. IMPLICATIONS: These animal studies indicate that there is a strong relationship between the level of nicotine intake and brain reward function. A high level of nicotine intake was more rewarding than a low level of nicotine intake and nicotine dependence was observed after long, but not short, access to nicotine. This powerful combination of nicotine reward and withdrawal makes it difficult to quit smoking. Blockade of nAChRs temporarily decreased nicotine intake, but this was followed by a large rebound increase in nicotine intake. Therefore, nAChR blockade might not decrease the use of combustible cigarettes or electronic cigarettes.

Enhancing effects of acute exposure to cannabis smoke on working memory performance.

Numerous preclinical studies show that acute cannabinoid administration impairs cognitive performance. Almost all of this research has employed cannabinoid injections, however, whereas smoking is the preferred route of cannabis administration in humans. The goal of these experiments was to systematically determine how acute exposure to cannabis smoke affects working memory performance in a rat model. Adult male (n = 15) and female (n = 16) Long-Evans rats were trained in a food-motivated delayed response working memory task. Prior to test sessions, rats were exposed to smoke generated by burning different numbers of cannabis or placebo cigarettes, using a within-subjects design. Exposure to cannabis smoke had no effect on male rats' performance, but surprisingly, enhanced working memory accuracy in females, which tended to perform less accurately than males under baseline conditions. In addition, cannabis smoke enhanced working memory accuracy in a subgroup of male rats that performed comparably to the worst-performing females. Exposure to placebo smoke had no effect on performance, suggesting that the cannabinoid content of cannabis smoke was critical for its effects on working memory. Follow-up experiments showed that acute administration of either Δ9-tetrahydrocannabinol (0.0, 0.3, 1.0, 3.0 mg/kg) or the cannabinoid receptor type 1 antagonist rimonabant (0.0, 0.2, 0.6, 2.0 mg/kg) impaired working memory performance. These results indicate that differences in the route, timing, or dose of cannabinoid administration can yield distinct cognitive outcomes, and highlight the need for further investigation of this topic.

Mifepristone decreases nicotine intake in dependent and non-dependent adult rats.

BACKGROUND: Addiction to tobacco and nicotine products has adverse health effects and afflicts more than a billion people worldwide. Therefore, there is an urgent need for new treatments to reduce tobacco and nicotine use. Glucocorticoid receptor blockade shows promise as a novel treatment for drug abuse and stress-related disorders. AIM: These studies aim to investigate whether glucocorticoid receptor blockade with mifepristone diminishes the reinforcing properties of nicotine in rats with intermittent or daily long access to nicotine. METHODS: The rats self-administered 0.06 mg/kg/inf of nicotine for 6 h per day, with either intermittent or daily access for 4 weeks before treatment with mifepristone. Daily nicotine self-administration models regular smoking, while intermittent nicotine self-administration models occasional smoking. To determine whether the rats were dependent, they were treated with the nicotinic acetylcholine receptor antagonist mecamylamine, and somatic signs were recorded. RESULTS: The rats with intermittent access to nicotine had a higher level of nicotine intake per session than those with daily access but only the rats with daily access to nicotine showed signs of physical dependence. Furthermore, mecamylamine increased nicotine intake during the first hour of access in rats with daily access but not in those with intermittent access. Mifepristone decreased total nicotine intake in rats with intermittent and daily access to nicotine. Moreover, mifepristone decreased the distance traveled and rearing in the open field test and operant responding for food pellets. CONCLUSION: These findings indicate that mifepristone decreases nicotine intake but this effect may be partially attributed to the sedative effects of mifepristone.

Age-Related Differences in Affective Behaviors in Mice: Possible Role of Prefrontal Cortical-Hippocampal Functional Connectivity and Metabolomic Profiles.

The differential expression of emotional reactivity from early to late adulthood may involve maturation of prefrontal cortical responses to negative valence stimuli. In mice, age-related changes in affective behaviors have been reported, but the functional neural circuitry warrants further investigation. We assessed age variations in affective behaviors and functional connectivity in male and female C57BL6/J mice. Mice aged 10, 30 and 60 weeks (wo) were tested over 8 weeks for open field activity, sucrose preference, social interactions, fear conditioning, and functional neuroimaging. Prefrontal cortical and hippocampal tissues were excised for metabolomics. Our results indicate that young and old mice differ significantly in affective behavioral, functional connectome and prefrontal cortical-hippocampal metabolome. Young mice show a greater responsivity to novel environmental and social stimuli compared to older mice. Conversely, late middle-aged mice (60wo group) display variable patterns of fear conditioning and with re-testing with a modified context. Functional connectivity between a temporal cortical/auditory cortex network and subregions of the anterior cingulate cortex and ventral hippocampus, and a greater network modularity and assortative mixing of nodes was stronger in young versus older adult mice. Metabolome analyses identified differences in several essential amino acids between 10wo mice and the other age groups. The results support differential expression of 'emotionality' across distinct stages of the mouse lifespan involving greater prefrontal-hippocampal connectivity and neurochemistry.

Age-related differences in affective behaviors in mice: possible role of prefrontal cortical-hippocampal functional connectivity and metabolomic profiles.

Introduction: The differential expression of emotional reactivity from early to late adulthood may involve maturation of prefrontal cortical responses to negative valence stimuli. In mice, age-related changes in affective behaviors have been reported, but the functional neural circuitry warrants further investigation. Methods: We assessed age variations in affective behaviors and functional connectivity in male and female C57BL6/J mice. Mice aged 10, 30 and 60 weeks (wo) were tested over 8 weeks for open field activity, sucrose preference, social interactions, fear conditioning, and functional neuroimaging. Prefrontal cortical and hippocampal tissues were excised for metabolomics. Results: Our results indicate that young and old mice differ significantly in affective behavioral, functional connectome and prefrontal cortical-hippocampal metabolome. Young mice show a greater responsivity to novel environmental and social stimuli compared to older mice. Conversely, late middle-aged mice (60wo group) display variable patterns of fear conditioning and during re-testing in a modified context. Functional connectivity between a temporal cortical/auditory cortex network and subregions of the anterior cingulate cortex and ventral hippocampus, and a greater network modularity and assortative mixing of nodes was stronger in young versus older adult mice. Metabolome analyses identified differences in several essential amino acids between 10wo mice and the other age groups. Discussion: The results support differential expression of 'emotionality' across distinct stages of the mouse lifespan involving greater prefrontal-hippocampal connectivity and neurochemistry.

AB-free kava enhances resilience against the adverse health effects of tobacco smoke in mice.

Tobacco smoke remains a serious global issue, resulting in serious health complications, contributing to the onsets of numerous preventive diseases, and imposing significant financial burdens. Despite regulatory policies and cessation measures aimed at curbing its usage, novel interventions are urgently needed for effective damage reduction. Our preclinical and pilot clinical studies showed that AB-free kava has the potential to reduce tobacco smoke-induced lung cancer risk, mitigate tobacco dependence, and reduce tobacco use. To understand the scope of its benefits in damage reduction and potential limitations, this study evaluated the effects of AB-free kava on a panel of health indicators in mice exposed to 2 - 4 weeks of daily tobacco smoke exposure. Our comprehensive assessments included global transcriptional profiling of the lung and liver tissues, analysis of lung inflammation, evaluation of lung function, exploration of tobacco nicotine withdrawal, and characterization of the causal PKA signaling pathway. As expected, Tobacco smoke exposure perturbed a wide range of biological processes and compromised multiple functions in mice. Remarkably, AB-free kava demonstrated the ability to globally mitigate tobacco smoke-induced deficits at the molecular and functional levels with promising safety profiles, offering a unique promise to mitigate tobacco smoke-related health damages. Further pre-clinical evaluation and clinical translation are warranted to fully harness the potential of AB-free kava in combating tobacco smoke-related harms.

The D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 decrease operant responding for nicotine and food and locomotor activity in male and female rats.

BACKGROUND: The reinforcing properties of nicotine play a critical role in smoking and vaping. There is a need for treatments that decrease the reinforcing properties of nicotine and thereby improve smoking and vaping rates. Dopamine plays a role in the reinforcing properties of nicotine, but little is known about the role of dopamine D2-like receptors in nicotine intake and whether there are sex differences in the effects of dopaminergic drugs on nicotine intake. AIM: The goal of the present studies was to investigate the effects of the D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 on nicotine self-administration in male and female rats. METHODS: The effects of flupentixol and L-741626 on operant responding for nicotine and food and locomotor activity in a small open field were investigated. RESULTS: There were no sex differences in baseline nicotine intake. The D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 decreased operant responding for nicotine. Blockade of D1/D2-like receptors and blockade of D2-like receptors also decreased operant responding for food and decreased locomotor activity. Flupentixol induced a greater decrease in operant responding for food in males than females. However, in the other tests, there were no sex differences in the effects of the dopamine receptor antagonists. CONCLUSIONS: Blockade of D1/D2-like receptors with flupentixol and D2-like receptors with L-741626 decreases nicotine and food intake in rats of both sexes. These compounds also decrease locomotor activity which might be indicative of a sedative effect.

An ethogram analysis of cutaneous thermal pain sensitivity and oxycodone reward-related behaviors in rats.

Inter-relationships between pain sensitivity, drug reward, and drug misuse are of considerable interest given that many analgesics exhibit misuse potential. Here we studied rats as they underwent a series of pain- and reward-related tests: cutaneous thermal reflex pain, induction and extinction of conditioned place preference to oxycodone (0.56 mg/kg), and finally the impact of neuropathic pain on reflex pain and reinstatement of conditioned place preference. Oxycodone induced a significant conditioned place preference that extinguished throughout repeated testing. Correlations identified of particular interest included an association between reflex pain and oxycodone-induced behavioral sensitization, and between rates of behavioral sensitization and extinction of conditioned place preference. Multidimensional scaling analysis followed by k-clustering identified three clusters: (1) reflex pain, rate of behavioral sensitization and rate of extinction of conditioned place preference (2) basal locomotion, locomotor habituation, acute oxycodone-stimulated locomotion and rate of change in reflex pain during repeated testing, and (3) magnitude of conditioned place preference. Nerve constriction injury markedly enhanced reflex pain but did not reinstate conditioned place preference. These results suggest that high rates of behavioral sensitization predicts faster rates of extinction of oxycodone seeking/reward, and suggest that cutaneous thermal reflex pain may be predictive of both.

An ethogram analysis of cutaneous thermal pain sensitivity and oxycodone reward-related behaviors in rats.

Inter-relationships between pain sensitivity, drug reward, and drug misuse are of considerable interest given that many analgesics exhibit misuse potential. Here we studied rats as they underwent a series of pain- and reward-related tests: cutaneous thermal reflex pain, induction and extinction of conditioned place preference to oxycodone (0.56 mg/kg), and finally the impact of neuropathic pain on reflex pain and reinstatement of conditioned place preference. Oxycodone induced a significant conditioned place preference that was extinguished throughout repeated testing. Correlations identified of particular interest included an association between reflex pain and oxycodone-induced behavioral sensitization, and between rates of behavioral sensitization and extinction of conditioned place preference. Multidimensional scaling analysis followed by k-clustering identified three clusters: (1) reflex pain and the rate of change in reflex pain response throughout repeated testing, (2) basal locomotion, locomotor habituation, and acute oxycodone-stimulated locomotion, and (3) behavioral sensitization, strength of conditioned place preference, and rate of extinction. Nerve constriction injury markedly enhanced reflex pain but did not reinstate conditioned place preference. These results support the notion that behavioral sensitization relates to the acquisition and extinction of oxycodone seeking/reward, but suggest that generally cutaneous thermal reflex pain poorly predicts oxycodone reward-related behaviors except for behavioral sensitization.