GABAergic cell transplants in the anterior cingulate cortex reduce neuropathic pain aversiveness.

Dysfunction of inhibitory circuits in the rostral anterior cingulate cortex underlies the affective (aversive), but not the sensory-discriminative features (hypersensitivity) of the pain experience. To restore inhibitory controls, we transplanted inhibitory interneuron progenitor cells into the rostral anterior cingulate cortex in a chemotherapy-induced neuropathic pain model. The transplants integrated, exerted a GABA-A mediated inhibition of host pyramidal cells and blocked gabapentin preference (i.e. relieved ongoing pain) in a conditioned place preference paradigm. Surprisingly, pain aversiveness persisted when the transplants populated both the rostral and posterior anterior cingulate cortex. We conclude that selective and long lasting inhibition of the rostral anterior cingulate cortex, in the mouse, has a profound pain relieving effect against nerve injury-induced neuropathic pain. However, the interplay between the rostral and posterior anterior cingulate cortices must be considered when examining circuits that influence ongoing pain and pain aversiveness.

Pain relief by supraspinal gabapentin requires descending noradrenergic inhibitory controls.

INTRODUCTION: Gabapentin regulates pain processing by direct action on primary afferent nociceptors and dorsal horn nociresponsive neurons. Through an action at supraspinal levels, gabapentin also engages descending noradrenergic inhibitory controls that indirectly regulate spinal cord pain processing. Although direct injection of gabapentin into the anterior cingulate cortex provides pain relief independent of descending inhibitory controls, it remains unclear whether that effect is representative of what occurs when gabapentin interacts at multiple brain loci, eg, after intracerebroventricular (i.c.v.) injection. METHODS: We administered gabapentin i.c.v. in a mouse model of chemotherapy (paclitaxel)-induced neuropathic pain. To distinguish spinal from supraspinally processed features of the pain experience, we examined mechanical hypersensitivity and assessed relief of pain aversiveness using an analgesia-induced conditioned place preference paradigm. RESULTS: Paclitaxel-treated mice showed a preference for a 100-µg i.c.v. gabapentin-paired chamber that was accompanied by reduced mechanical allodynia, indicative of concurrent engagement of descending controls. As expected, the same dose in uninjured mice did not induce place preference, demonstrating that gabapentin, unlike morphine, is not inherently rewarding. Furthermore, a lower dose of supraspinal gabapentin (30 µg), which did not reverse mechanical allodynia, did not induce conditioned place preference. Finally, concurrent injections of i.c.v. gabapentin (100 µg) and intrathecal yohimbine, an α2-receptor antagonist, blocked preference for the gabapentin-paired chamber. CONCLUSION: We conclude that pain relief, namely a reduction of pain aversiveness, induced by supraspinal gabapentin administered by an i.c.v. route is secondary to its activation of descending noradrenergic inhibitory controls that block transmission of the "pain" message from the spinal cord to the brain.

Spatial and temporal processing of single auditory cortical neurons and populations of neurons in the macaque monkey.

The auditory cortex is known to be a necessary neural structure for the perception of acoustic signals, particularly the spatial location and the temporal features of complex auditory stimuli. Previous studies have indicated that there is no topographic map of acoustic space in the auditory cortex and it has been proposed that spatial locations are represented by some sort of population code. Additionally, in spite of temporal processing deficits being one of the hallmark consequences of normal aging, the temporal coding of acoustic stimuli remains poorly understood. This report will address these two issues by discussing the results from several studies describing responses of single auditory cortical neurons in the non-human primate. First, we will review studies that have addressed potential spike-rate population codes of acoustic space in the caudal belt of auditory cortex. Second, we will present new data on the neuronal responses to gap stimuli in aged monkeys and compare them to published reports of gap detection thresholds. Together these studies indicate that the alert macaque monkey is an excellent model system to study both spatial and temporal processing in the auditory cortex at the single neuron level.

Hierarchical and serial processing in the spatial auditory cortical pathway is degraded by natural aging.

The compromised abilities to localize sounds and to understand speech are two hallmark deficits in aged individuals. The auditory cortex is necessary for these processes, yet we know little about how normal aging affects these early cortical fields. In this study, we recorded the spatial tuning of single neurons in primary (auditory cortex, A1) and secondary (caudolateral field, CL) auditory cortical areas in young and aged alert rhesus macaques. We found that the neurons of aged animals had greater spontaneous and driven activity, and broader spatial tuning compared with those of younger animals. Importantly, spatial tuning was not sharpened between A1 and CL in aged monkeys as it is in younger monkeys. This implies that a major effect of normal aging is a degradation of the hierarchical processing between serially connected cortical areas, which could be a key contributing mechanism of the general cognitive decline that is commonly observed in normal aging.