Roles of the anterior cingulate cortex and medial thalamus in short-term and long-term aversive information processing.

BACKGROUND: The anterior cingulate cortex (ACC) and medial thalamus (MT) are two of the main components of the medial pain pathway that subserve the affective aspect of pain. The hypothesis of the present study was that the ACC is involved in short-term aversive information processing and that the MT is critical for encoding unconditioned nociceptive information. The roles of these two components in short-term and long-term aversive information processing was investigated using a step-through inhibitory avoidance task. RESULTS: Behavioral training began 1 week after surgery, in which radiofrequency lesions of the ACC or MT were performed. The retention tests were conducted 30 s (short-term) or 24 h (long-term) after training. Pretraining radiofrequency lesions of the ACC impaired performance in the 30 s, but not 24 h, retention test. Microinfusions of lidocaine into the ACC immediately after training impaired performance in the retention test conducted 10 min later. Pretraining radiofrequency lesions of the MT impaired performance in both the 30 s and 24 h retention tests. However, posttraining, but not pretest, microinfusions of lidocaine into the MT impaired performance in the 24 h retention test. CONCLUSIONS: These results suggest that the ACC may play an important role in short-term, but not long-term, nociceptive information processing. In contrast, the MT may be important for the consolidation of nociceptive information storage.

Anxiety- and depressive-like responses and c-fos activity in preproenkephalin knockout mice: oversensitivity hypothesis of enkephalin deficit-induced posttraumatic stress disorder.

The present study used the preproenkephalin knockout (ppENK) mice to test whether the endogenous enkephalins deficit could facilitate the anxiety- and depressive-like symptoms of posttraumatic stress disorder (PTSD). On Day 1, sixteen wildtype (WT) and sixteen ppENK male mice were given a 3 mA or no footshock treatment for 10 seconds in the footshock apparatus, respectively. On Days 2, 7, and 13, all mice were given situational reminders for 1 min per trial, and the freezing response was assessed. On Day 14, all mice were tested in the open field test, elevated plus maze, light/dark avoidance test, and forced swim test. Two hours after the last test, brain tissues were stained to examine c-fos expression in specific brain areas. The present results showed that the conditioned freezing response was significant for different genotypes (ppENK vs WT). The conditioned freezing effect of the ppENK mice was stronger than those of the WT mice. On Day 14, the ppENK mice showed more anxiety- and depressive-like responses than WT mice. The magnitude of Fos immunolabeling was also significantly greater in the primary motor cortex, bed nucleus of the stria terminalis-lateral division, bed nucleus of the stria terminalis-supracapsular division, paraventricular hypothalamic nucleus-lateral magnocellular part, central nucleus of the amygdala, and basolateral nucleus of the amygdala in ppENK mice compared with WT mice. In summary, animals with an endogenous deficit in enkephalins might be more sensitive to PTSD-like aversive stimuli and elicit stronger anxiety and depressive PTSD symptoms, suggesting an oversensitivity hypothesis of enkephalin deficit-induced PTSD.

Nocifensive behaviors components evoked by brief laser pulses are mediated by C fibers.

Nocifensive behavior involves several response elements that have been used to assess neuropharmacological effects in different animal models of pain. Our previous analysis of laser-evoked nocifensive behaviors suggested that hierarchically organized responses in the nocifensive motor system are recruited in varying degrees by noxious stimuli of different intensities. Nocifensive behaviors can be differentially elicited and mediated by different classes of nociceptors. Thus, the aim of this study was to test the hypothesis that nocifensive behavioral elements elicited by brief laser pulse stimuli are mediated by C nociceptors. Laser-evoked cortical potentials and nocifensive behavior elements were recorded concurrently. As stimulus energy increased, rats exhibited a larger number of different responses and a greater frequency of each response element. Applying the neurotoxin, capsaicin, which selectively inhibits C fibers, to the sciatic nerves of rats, differentially blocked nocifensive behavioral components of flinch, withdrawal and licking but not non-nocifensive responses, namely movement and head turning. Based on these results we suggest that flinch, withdrawal and licking are mediated by C fibers, which are temporally associated with the nocifensive motor system as well as spinal and cortical evoked potentials. These results link hierarchically organized nocifensive responses and the afferent C fibers in the nocifensive motor system.

A quantitative method for assessing of the affective component of the pain: conditioned response associated with CO2 laser-induced nocifensive reaction.

Sensory and affective components are included in the overall behavioral manifestation in a nocifensive reaction. We have developed a behavioral model using classical conditioning to differentiate the affective component from the sensory responses following a thermal noxious stimulus. In laser-pain conditioning, free moving rats were trained to associate a tone (conditioned stimulus, CS) and short CO2 laser pulsation (unconditioned stimulus, US). A monotonous tone (800 Hz, 0.6 s) was delivered through a loudspeaker as the CS. CO(2) laser pulses (5 W at 100 ms in duration) applied to the hind paw were adopted as the US. The CS-US interval was 0.5 s. The conditioned responses as quantitatively measured by their body movement were developed over a period of 40 CS-US pairings. These conditioned responses were found retained when the rats were tested by presenting CS alone, immediate to and 24 h subsequent to training. The conditioned responses however diminished significantly following both morphine and buspirone treatment. This method demonstrated that neutral auditory stimuli could form association with unlearned nocifensive responses evoked by noxious CO2 laser pulses stimuli. Thus, the assessment of conditioned response may be a valuable tool for the measurement of the affective component of nociception.

Contribution of the anterior cingulate cortex to laser-pain conditioning in rats.

The emotional component of nociception is seldom distinguished from pain behavioral testing. The aim of the present study was to develop a behavioral test that indicates the emotional pain responses using the classical conditioning paradigm. The role of the anterior cingulate cortex (ACC) in the process of this pain conditioning response was also evaluated. In laser-pain conditioning, free moving rats were trained to associate a tone (conditioned stimulus, CS) and short CO(2) laser pulsation (unconditioned stimulus, US). Monotonous tone (800 Hz, 0.6 s) was delivered through a loud-speaker as CS. CO(2) laser pulses (5 W at 50 or 100 ms in duration) applied to the hind paw was adopted as US. The CS-US interval was 0.5 s. Laser-pain conditioning was developed during 40 CS-US pairings. CS and US pairing with 100-ms laser pulse stimuli was more effective in establishing conditioning responses than that of 50-ms stimuli. The conditioning responses remained, tested by presenting CS alone, immediate to and 24 h subsequent to training. The performance of laser-pain conditioning was significantly reduced after bilateral lesioning of the ACC. Similar results were also obtained by bilateral lesions of the amygdala. The conditioning responses were also diminished following morphine treatment. The association between a neutral stimulus and a noxious stimulus could be demonstrated in a Pavlovian conditioning test in free moving rats. Thus, the conditioned response may be employed as a measure of the emotional component of the nociception. It is also suggested that the ACC may play an important role in mediating this conditioning effect.

Potentiation of local field potentials in the anterior cingulate cortex evoked by the stimulation of the medial thalamic nuclei in rats.

The limbic thalamus and cingulate cortex are essential components in mediating the affective component of pain responses. In the present study, we examined the excitatory properties of medial thalamus (MT)-evoked field potentials in the anterior cingulated cortex (ACC). We also examined the effects of paired pulses and brief tetanic stimuli of the MT. The aim of this study was to determine whether nociceptive inputs to medial thalamic afferents cause plastic changes in the ACC. In alpha-chloralose (50 mg/kg, i.v.) anaesthetized rats, tungsten microelectrodes were used to stimulate the MT and to record field potentials in the ACC. The locations of MT were identified by searching and examining their responses to peripheral noxious stimuli. Early negative (about 4.7 ms latency) and late positive (about 11.7 ms) potentials could be evoked in the ACC by MT stimuli. The evoked field potentials were potentiated by prepulse stimulation. Maximal paired pulse facilitation (509+/-51%) was produced in 80-150 ms interpulse intervals. Evoked field potentials were also potentiated (28.8+/-6.3% and 29.6+/-5.9%, respectively) by low (10 Hz/10 s) and high (100 Hz/2s/2x) frequency tetanic stimulation of the MT, with a duration maintained for about 90 s and 120 min, respectively. The potentiation of MT-evoked ACC potentials provides a neural basis for synaptic plasticity, which may be essential for the establishment of pain-initiated conditioning behavior and affective responses to noxious stimuli.