Chronic pain assessment from bench to bedside: lessons along the translation continuum.

The first step to providing effective healthcare is accurate assessment and diagnosis. The importance of accurate assessment is particularly important for chronic pain, given its subjective and multidimensional nature. The purpose of the current review is to discuss the dilemma of chronic pain assessment within a translational framework. First, assessment issues specific to chronic pain will be introduced along the entire continuum of translational activities. Important barriers along the continuum include inconsistent measurement of pain, possibly inaccurate preclinical models, and other practical limitations such as time, cost, and training. Second, the review will highlight promising areas worth further consideration in research and practice to bridge some of the gaps that currently impede effective chronic pain assessment and care. Specifically, consideration will be given to observational, biological, and technology-driven measures of chronic pain.

Temporal patterns of rat behaviour in the central platform of the elevated plus maze. Comparative analysis between male subjects of strains with different basal levels of emotionality.

We have analyzed the temporal patterns of behaviour of male rats of the Wistar and DA/Han strains on the central platform of the elevated plus maze. The ethogram encompassed 10 behavioural elements. Durations, frequencies and latencies showed quantitative differences as to walking and sniffing activities. Wistar rats displayed significantly lower latency and significantly higher durations and frequencies of walking activities. DA/Han rats showed a significant increase of sniffing duration. In addition, DA/Han rats showed a significantly higher amount of time spent in the central platform. Multivariate T-pattern analysis revealed differences in the temporal organization of behaviour of the two rat strains. DA/Han rats showed (a) higher behavioural complexity and variability and (b) a significantly higher mean number of T-patterns than Wistar rats. Taken together, T-pattern analysis of behaviour in the centre of the elevated plus maze can noticeably improve the detection of subtle features of anxiety related behaviour. We suggest that T-pattern analysis could be used as sensitive tool to test the action of anxiolytic and anxiogenic manipulations.

Repeated forced swim stress differentially affects formalin-evoked nociceptive behaviour and the endocannabinoid system in stress normo-responsive and stress hyper-responsive rat strains.

Repeated exposure to a homotypic stressor such as forced swimming enhances nociceptive responding in rats. However, the influence of genetic background on this stress-induced hyperalgesia is poorly understood. The aim of the present study was to compare the effects of repeated forced swim stress on nociceptive responding in Sprague-Dawley (SD) rats versus the Wistar Kyoto (WKY) rat strain, a genetic background that is susceptible to stress, negative affect and hyperalgesia. Given the well-documented role of the endocannabinoid system in stress and pain, we investigated associated alterations in endocannabinoid signalling in the dorsal horn of the spinal cord and amygdala. In SD rats, repeated forced swim stress for 10 days was associated with enhanced late phase formalin-evoked nociceptive behaviour, compared with naive, non-stressed SD controls. In contrast, WKY rats exposed to 10 days of swim stress displayed reduced late phase formalin-evoked nociceptive behaviour. Swim stress increased levels of monoacylglycerol lipase (MAGL) mRNA in the ipsilateral side of the dorsal spinal cord of SD rats, an effect not observed in WKY rats. In the amygdala, swim stress reduced anandamide (AEA) levels in the contralateral amygdala of SD rats, but not WKY rats. Additional within-strain differences in levels of CB1 receptor and fatty acid amide hydrolase (FAAH) mRNA and levels of 2-arachidonylglycerol (2-AG) were observed between the ipsilateral and contralateral sides of the dorsal horn and/or amygdala. These data indicate that the effects of repeated stress on inflammatory pain-related behaviour are different in two rat strains that differ with respect to stress responsivity and affective state and implicate the endocannabinoid system in the spinal cord and amygdala in these differences.

Comparison of the validity of the use of the spontaneously hypertensive rat as a model of attention deficit hyperactivity disorder in males and females.

The spontaneously hypertensive rat (SHR) is a commonly used and well-studied rodent model of attention deficit hyperactivity disorder (ADHD). Sex differences in the cognitive symptoms of ADHD are reported. However, the female SHR rat is much less studied than its male counterpart. The goal of the current study was to assess the validity of the SHR rodent model of ADHD by examining attentional performance, inhibitory control, and hyperactivity in both male and female SHR rats. Adult SHR and control Wistar-Kyoto rats were trained on the 5-choice serial reaction time task, a self-paced test of attention and inhibitory control. This task requires animals to identify the location of a brief light stimulus among five possible locations under several challenging conditions. Analyses of percent correct revealed that attentional performance in SHR females was not significantly different from control females, whereas attentional performance in SHR males was significantly different from control males. Analyses of the number of premature responses revealed that SHR rats made more inhibitory control errors than did control rats and that this decrease in inhibitory control was present in both SHR males and females. Analyses of activity in the open field revealed that SHR rats were more hyperactive than were control rats and that this increased hyperactivity was present in both SHR males and females. The current findings have implications for the study of sex differences in ADHD and for the use of SHR rats as a model of ADHD in females.

Schedule-induced polydipsia in the spontaneously hypertensive rat and its relation to impulsive behaviour.

Eight Spontaneously Hypertensive Rat (SHR), 8 Wistar-Kyoto (WKY) and 8 Wistar rats, all male, maintained at 80-85% of their free-feeding weight by controlled access to food, were exposed to a series of fixed time (FT) schedules whereby food pellets were regularly delivered regardless of the animals' behaviour. The FT values used were 9, 15, 30, 60, 120 and 180 s, with the order of presentation of the schedules among the animals being counterbalanced (except under the FT 120-s and 180-s schedules, which were successively presented as the last two of the series). Due to freely available access to water, the animals developed schedule-induced drinking under all FT schedules, marked by the characteristic bitonic function that relates the number of licks and amount of water drunk to the length of the inter-food interval. Wistar and WKY rats displayed maximum drinking under an FT 15-s schedule, with WKY rats registering lower quantities across all FT values. Among SHR rats, maximum schedule-induced polydipsia was observed under the FT 30-s schedule, with a rightward shift in the bitonic function compared to controls. For long FT values, the temporal distribution of licks within inter-food intervals was shifted slightly towards the right in the SHR rats. In a subsequent study, only the SHR and Wistar rats were used, and the animals were exposed to a delay-discounting procedure. The rats were faced with successive choices, in which they could choose between an immediate reward of one food pellet and another of four food pellets at a delay of 3, 6, 12 or 24s. In the case of the longer delays, SHR rats chose the immediate reward of lower magnitude more often than did their Wistar counterparts, and also committed a greater number of omissions during the forced-choice trials of the procedure. The results indicate that differences in schedule-induced polydipsia are related to indexes of cognitive rather than motor impulsivity, a finding in line with the theoretical idea that adjunctive behaviour is linked to operant reinforcement processes.

Aging effects on elevated plus maze behavior in spontaneously hypertensive, Wistar-Kyoto and Sprague-Dawley male and female rats.

Male and female spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats were assessed at one of two ages (postnatal day 74 or 346) for open field locomotor activity and anxiety-related behavior in the elevated plus maze (EPM). In general, the SHR displayed the least anxiety-related behavior, an effect that was magnified with age. At 11 months of age, the SHR more frequently entered and remained longer in the open arms than either the SD or the WKY strains. EPM behavior of the WKY strain was much less affected by age than that of the SD strain which displayed increased anxiety-related behavior with age. At the younger age, the typical sex effects were apparent; specifically, females exhibited a shorter duration in the closed arms. While the SHR were the most active strain in the EPM at both ages, they were more active in the open field only at the older age. In general, age-related changes in open field activity mirrored those of the EPM. These results provide a more comprehensive illustration of aging-related behavioral changes in male and female SHR, WKY and SD rats.

Investigatory behavior of a novel conspecific by Wistar Kyoto, Wistar and Sprague-Dawley rats.

The assumption was made that investigatory behaviors (i.e., ano-genital and general body sniffing) of a female conspecific by a mature male rat, has positive hedonic characteristics. Because reduced interest in pleasurable events (i.e., anhedonia) is diagnostically related to depressive behavior, the hypothesis was advanced that less investigatory behavior would be observed in an animal model of depression, namely the Wistar Kyoto (WKY) rat strain. In Experiment 1, WKY, Wistar and Sprague-Dawley male rats were subjected, in the first test series, to three consecutive 2-min exposures to one intruder stimulus female, followed later by another three consecutive 2-min exposures to a second stimulus intruder female. On the second test series, 24 h later, the male rats were exposed to one female for 2 min, followed 6 min later to another 2-min exposure to another stimulus female. Half the male subjects were subjected to tail shock stress 2 h before the first test series. All males demonstrated a habituation of the investigatory response to the same stimulus female, but a dishabituation when subsequently exposed to a new stimulus female. Only WKY rats, exposed to prior stress, revealed a significant reduction in investigatory behavior. In Experiment 2, using only WKY and Wistar rats, a factorial design was used to observe any differences between two stressors, namely tail shock and water restraint, and also to observe possible differences in investigatory behavior towards male vs. female intruder rats. Restraint stress and shock stress elicited significant reductions in investigatory behavior for WKY rats, but not Wistar rats, when confronted with female intruder rats. Male intruders elicited more freezing behavior, as well as aggressive defensive fighting behavior from resident male rats. The results are interpreted to suggest that the significant decrease in investigatory behavior towards a female intruder, which was observed primarily in stressed WKY males, reflects the presence of anhedonia in stressed WKY rats, and reinforces our assertion that the WKY rat strain represents a useful animal model of depressive behavior.

Strain difference in behavioral response to a new environment in rats.

Locomotor activity in rats throughout a 24-hour period in a new environment was examined for strain differences and for the capacity for adaptation to that environment. Fischer 344 rats (F344), spontaneously hypertensive rats (SHR) and Wistar normotensive Kyoto rats (WKY) were used. The horizontal locomotor activity of individual rats was measured by photocell-utilizing activity-recording devices. The locomotor activity counts on the second day, after 1 day of adaptation, were compared with those after 5 days of adaptation (on the sixth day). In WKY, there was no difference in activity at any period of the day between the second and sixth days. In SHR, the locomotor activity on the second day between 6:00 h and 9:00 h (in the light phase) and between 24:00 h and 3:00 h (in the dark phase) was higher than on the sixth day. In F344, the locomotor activity on the second day between 18:00 h and 2:00 h was higher than on the sixth day. The capacity for adaptation in SHR and F344 was thus poorer than in WKY. The poor adaptation in SHR and F344 was similar to that in depressive patients induced by moving house. These findings suggested that SHR or F344 were suitable for depression research.

The spontaneously hypertensive rat (SHR) as an animal model of childhood hyperactivity (ADHD): changed reactivity to reinforcers and to psychomotor stimulants.

Childhood hyperactivity (attention-deficit hyperactivity disorder, ADHD) is a behavior disorder affecting 2-6% of grade-school children. The main symptoms are attention problems and hyperkinesis. The disorder is commonly treated with psychomotor stimulants, usually methylphenidate hydrochloride (ritalin) or d-amphetamine. Neither the cause of the disorder nor the basis of the effectiveness of the drug treatment is well understood. Differences in reinforcement processes have been implicated as part of the underlying problem. The main purpose of the present research was to investigate reinforcement processes and motor characteristics with and without stimulant medication in SHR, as an animal model of ADHD, and WKY controls, its normoactive progenitor strain. SHR behavior turned out to be more sensitive to immediate reinforcement and proportionately less sensitive to delayed reinforcement when compared to the behavior of WKY, as demonstrated by systematic changes in rates of responding throughout fixed-interval schedules of reinforcement of bar-presses by water. The psychomotor stimulants weakened the control by immediate reinforcers and strengthened the control by delayed reinforcers, with the effect of the drugs being more pronounced in WKY than in SHR. The results are consistent with clinical observations that ADHD children are less willing than others to accept "delayed gratification" and that methylphenidate increases the control of delayed reward over their behavior.