Blockade of dopamine D2 receptors disrupts intrahippocampal connectivity and enhances pain-related working memory deficits in neuropathic pain rats.

BACKGROUND: Dopamine (DA) is thought to be important to local hippocampal networks integrity during spatial working memory (sWM) processing. Chronic pain may contribute to deficient dopaminergic signalling, which may in turn affect cognition. However, the neural mechanisms that determine this impairment are poorly understood. Here, we evaluated whether the sWM impairment characteristic of animal models of chronic pain is dependent on DA D2 receptor (D2r) activity. METHODS: To address this issue, we implanted multichannel arrays of electrodes in the dorsal and ventral hippocampal CA1 field (dvCA1) of rats and recorded the neuronal activity during a classical delayed food-reinforced T-maze sWM task. Within-subject behavioural performance and patterns of dorsoventral neural activity were assessed before and after the onset of persistent neuropathic pain using the spared nerve injury (SNI) model. RESULTS: Our results show that the peripheral nerve lesion caused a disruption in sWM and hippocampus spike activity and that disruption was maximized by the systemic administration of the D2r antagonist raclopride. These deficits are strictly correlated with a selective disruption of hippocampal theta-oscillations. Particularly, we found a significant decrease in intrahippocampal CA1 field connectivity level. CONCLUSIONS: Together, these results suggest that disruption of the dopaminergic balance in the intrahippocampal networks may be important for the development of cognitive deficits experienced during painful conditions. SIGNIFICANCE: This study provides new insights into the role of D2r in the manifestation of pain-related sWM deficits. Our findings support that selective blockade of D2r produces a significant decrease in intrahippocampal connectivity mediated by theta-oscillations, and amplifies pain-related sWM deficits. These results suggest that further characterization of intrahippocampal dopaminergic modulation may be clinically relevant for the understanding of cognitive impairments that accompanies nociceptive stressful conditions.

Cognitive impairment of prefrontal-dependent decision-making in rats after the onset of chronic pain.

Forced choice between alternative options of unpredictable outcome is a complex task that requires continual update of the value associated with each option. Prefrontal areas such as the orbitofrontal cortex (OFC) have been shown to play a major role in performance on ambiguous decision-making tasks with substantial risk component, broadly named as "gambling tasks." We have recently demonstrated that rats display complex decision-making behavior in a rodent gambling task based on serial choices between rewards of different value and probability. This rodent task retains many of the key characteristics of the human Iowa Gambling Task (IGT), and performance in this novel task is also disrupted by OFC or amygdalar lesioning. In the present study we addressed if rat models of chronic pain would have impaired performance in this gambling task, since it is already known that the IGT response patterns of human pain patients are comparable to individuals with OFC lesions. We found that animals with a monoarthritic inflammatory model of chronic pain systematically preferred the lever associated with larger but infrequent rewards. In addition, we measured the neurochemical content of the OFC, amygdala and nucleus accumbens using HPLC, and found that in prolonged chronic pain animals there was a decrease in the tonic levels of dopamine, DOPAC (3,4-hydroxyphenyl-acetic acid) and 5-HIAA (5-hydroxyindole-3-acetic acid) in the OFC. This is the first report of the effect of chronic pain in rat decision-making processes and supports the notion that pain may have profound effects on the functioning of the reward-aversion circuitry relevant to strategic planning.

Orbitofrontal cortex lesions disrupt risk assessment in a novel serial decision-making task for rats.

Neurobiological mechanisms of decision-making have been shown to be modulated by a number of frontal brain regions. Among those areas, the orbitofrontal cortex (OFC) is thought to play an important role in the decision of behavioral actions when faced with alternative options of ambiguous outcome. Here we present a novel neurobehavioral task to study affective decision-making in the rat, based on evaluation of consecutive choices between two levers associated with rewards of different value and probability. Two groups of animals were studied; a sham control group (n=6) and an OFC-lesioned group (n=7). In the first 30 trials both groups had similar preference patterns but at the end of the 90 trials of the task both groups developed specific preferences. The control group systematically preferred the lever associated with smaller but more reliable rewards (low risk lever) while the OFC lesion group preferred the high risk lever (index of preference of 0.21+/-0.21 vs. -0.45+/-0.10; t-test, P<0.05). Analysis of choice persistence (i.e. choosing the same lever in consecutive trials) suggests that the OFC-lesioned group became less sensitive to risk, seeking large rewards irrespective of their success probability.

Immediate reorganization of the rat somatosensory thalamus after partial ligation of sciatic nerve.

Nerve injury can result in neuropathic pain, which persists after the injury and may occur after healing is completed. The long-term central reorganization associated with neuropathic pain has been previously studied in animal models. The immediate effects of nerve injury on central representation, however, are poorly understood. We examined the population response properties of closely neighboring neurons located in the hindlimb representation area of the somatosensory thalamus. Changes in the neuronal population properties were characterized before, during, and after (up to 6 hours) partial ligation of the sciatic nerve in the rat. Changes in these properties were observed within minutes after nerve injury. There were changes in neuronal class and receptive field size, emergence of new receptive fields, receptive fields observed before ligation disappeared temporarily after ligation, and changes in number of spikes evoked by the same stimulus. The rates of these changes in central representation were essentially zero before ligation, maximal within minutes after ligation, and decreased to a steady sustained rate of change within 1 to 2 hours. The incidence of functional connectivity, as measured by cross-correlations, remained unchanged. However, the strength of functional connectivity increased after ligation. The results show immediate reorganization of lateral thalamic networks with peripheral nerve damage. When the population response is considered as the underlying code, this reorganization does not reflect the behavioral manifestations of hyperalgesia and allodynia, even though some of the individual neuronal responses do reflect properties consistent with the hyperalgesia and allodynia reported within the same time frame after nerve injury in the rat.

Spinomedullary pathways in the pigeon (Columba livia): differential involvement of lamina I cells.

The lamina I (marginal zone) of the spinal cord dorsal horn is an important site for pain processing. In mammals, lamina I neurons have been shown to constitute a heterogeneous population made up of four morphological groups with particular neurochemical nature, supraspinal connection patterns, and nociceptive response properties. In order to obtain a comparative view of the mechanisms of nociceptive processing, the analysis of the structural morphology and supraspinal connectivity of lamina I neurons was, in this study, extended to the avian family. Cholera toxin subunit B (CTb) was injected in the nucleus tractus solitarius (NTS), nucleus centralis medullae pars dorsalis (Cnd), and the dorsolateral portion of the nucleus reticularis lateralis (RLlat) of the pigeon (Columba livia), areas equivalent to the rat caudal medulla oblongata lamina I targets, which have been shown to receive differential projections from all cell groups present in lamina I of mammals. In the pigeon, lamina I cells project to the three medullary regions and present the same morphology of spinomedullary lamina I cells of mammals: the spinal-NTS and the spinal-RLlat pathways originated from fusiform, pyramidal, and flattened neurons, and the spinal-Cnd pathway from multipolar, pyramidal, and flattened neurons. Furthermore, the relative participation of each lamina I cell type in each pathway was found to be similar to that previously observed in the rat. The observed similarities on the anatomical organization of lamina I neurons in mammalian and avian species can be taken as a phylogenetic indication of the importance of the nociceptive circuitry centered in lamina I.

Structural characterization of marginal (lamina I) spinal cord neurons in the cat: a Golgi study.

The neuronal population of the spinal cord lamina I (marginal zone) was structurally characterized, in the cat, by the use of the Golgi method complemented by multivariate analysis of morphometric data. Four cell types were identified, two of them including two subtypes. Fusiform cells accounted for 43% of impregnated cells and presented flame-shaped rostrocaudally elongated perikarya and bipolar, either strictly longitudinal (fusiform A; 37%) or longitudinal and ventral (fusiform B; 6%) dendritic arbors with numerous short-pedicled spines. Fusiform cells preferentially occupied the lateral one-third of lamina I. Multipolar cells (22%) had ovoid perikarya with bulging surfaces and numerous primary dendritic trunks. Two subtypes could be distinguished: multipolar A cells (12%) with highly ramified dendrites covered with variably shaped spines and multipolar B cells (10%) with looser and less spiny dendritic arbors expanded for longer distances. Multipolar cells were more commonly found in the medial half of lamina I. Flattened cells (16%) possessed discoid perikarya flattened across the dorsoventral axis and aspiny, scarcely ramified dendritic arbors distributed horizontally within lamina I. They predominated in the intermediate one-third of the lamina. Pyramidal cells had triangular prismatic perikarya partially encased in the white matter overlying lamina I. They represented 19% of the impregnated neurons and were located along the entire lateromedial extent of the lamina. Each neuronal type included a few cells with perikarya and dendritic arbors three times larger than the rest. These so-called giant cells amounted to 6% of the entire lamina I neuronal population. According to the present data, the neuronal population of the spinal cord lamina I of the cat strongly resembles that of the rat (Lima and Coimbra, J. Comp. Neurol. 244:53-71, 1986), which strengthens the functional relevance of this structural classification.