| The pain experience includes a sensory-discriminative and an affective-motivational component. The affective aspect of pain is made up of feeling of unpleasantness tightly coupled to stimulus, also termed primary unpleasantness and emotions associated with the future implications, termed secondary affect. Patients with chronic pain in clinic suffer from much more affective disturbance than pain itself. Recently, increasing attention is paid to the study on mechanisms underlying pain affect. The present study consists of three parts.1. Formalin-induced conditioned place avoidance rat modelIntraplantar injection of formalin into hindpaw of rats produced tonic pain, which is a widely used animal model. By means of a combination of rat formalin-induced pain model with the place-conditioning paradigm, Johansen et al developed a novel rat model to distinguish the "pain emotion" from "pain sensation". When formalin was repetitively injected into the hindpaw at the formalin-paired context, rats avoided the pain environment if alternative choice is provided. The learning behavior is called "formalin-induced conditioned place avoidance (F-CPA)", which directly reflects pain affec produced by the nociceptive stimulus. F-CPA model was used in the present study. The conditioning training was performed on the rat for a successive 6 days. On the pre-conditioning day, no initial preference to any compartment was observed in formalin-treated group (524.1 ± 15.3 s conditioned compartment vs. 526.6 ± 13.6 s unconditioned compartment; Student's t test, P >0.05) and saline-treated group (514.4 ± 13.4 s conditioned compartment vs 523.2 ± 13.3 s unconditioned compartment; Student's t test, P >0.05). On the post-conditioning day, for the formalin-treated group, rats spent significantly less time in the conditioned compartment after conditioning than that before conditioning (420 ± 18.4 post-conditioning s vs 524.1 ± 15.3 s pre-conditioning; Student's t test, p<0.001). Aside from the avoidance behavior, the rat appeared rigorous affective behaviors, such as escaping, exploring violently, freezing, irritation and shallow breathing. In the saline-treated group, animals exhibited no avoidance to the conditioned environment (487.1 ± 14.9 s post-conditioning vs 514.4 ± 13.4 s pre-conditioning s; Student's t test, P>0.05). The conditioning scores of F-CPA in the formalin-treated group and the saline-treated group were 105.1 ± 21.5 sec and 27.3 ± 16.5 sec, respectively. The conditioning score of formalin-treated group is significantly higher than that of saline-treated group(Student's t test, P<0.05). The results demonstrated that conditioned place paradigm plus with tonic pain rat model resulted in F-CPA behavior accompanying by pain-evoked aversive affect.2.Fos expression in pain affect-related central structuresUsing F-CPA retrieval task combining with Fos immunohistochemistry, we mapped the central structures involved in "pain affect". Rats were trained for a successive 4 days. The time spent by rats in formalin-treated group in the conditioning compartment before and after conditioning was 517.4 ± 12 sec and 446.1 ± 15.8 sec, respectively (Student's t test, p<0.001). When retrieved in the conditioned compartment, the rats with F-CPA produced rigorous "affect-like behaviors". Resultantly, much more Fos-LI neurons was observed in anterior cingulate cortex, retrosplenial cortex, insular cortex, parietal cortex area II, frontal cortex area I - III, claustrum, lateral septal area, amygdala, dorsomedial hypothalamic nucleus, central medial nucleus, paraventricular nucleus, superior colliculus, inferior colliculus and periaqueductal gray. The results for the first time mapped the brain regions associated with processing of "pain affect" in rats. Fos expression was found in many cortical and subcortical brain regions; whereas absent in the dorsal horn of spinal cord following pain retrieval. The results further suggest that multiple supraspinal structures are involving in secondary pain a...
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