Effects of Electrical Stimulation of NAc Afferents on VP Neurons’ Tonic Firing

Afferents from the nucleus accumbens (NAc) are a major source of input into the ventral pallidum (VP). Research reveals that these afferents are GABAergic, however, stimulation of these afferents induces both excitatory and inhibitory responses within the VP. These are likely to be partially mediated by enkephalin and substance P (SP), which are also released by these afferents, and are known to modulate VP neurons. However, less is known about the potentially differential effects stimulation of these afferents has on subpopulations of neurons within the VP and the cellular mechanisms by which they exert their effects. The current study aimed to research this further using brain slices containing the VP, stimulation of the NAc afferents, and multi-electrode array (MEA) recordings of their VP targets. Stimulation of the NAc afferents induced a pause in the tonic firing in 58% of the neurons studied in the VP, while 42% were not affected. Measures used to reveal the electrophysiological difference between these groups found no significant differences in firing frequency, coefficient of variation, and spike half-width. There were however significant differences in the pause duration between neurons in the dorsal and ventral VP, with stimulation of NAc afferents producing a significantly longer pause (0.48 ± 0.06 s) in tonic firing in dorsal VP neurons, compared to neurons in the ventral VP (0.21 ± 0.09 s). Pauses in the tonic firing of VP neurons, as a result of NAc afferent stimulation, were found to be largely mediated by GABAA receptors, as the application of picrotoxin significantly reduced their duration. Opioid agonists and antagonists were found to have no significant effects on the pause in tonic activity induced by NAc afferent stimulation. However, NK-1 receptor antagonists caused significant decreases in the pause duration, suggesting that SP may contribute to the inhibitory effect of NAc afferent stimulation via activation of NK-1 receptors.

Distinct mechanisms of signal processing by lamina I spino-parabrachial neurons

Lamina I spino-parabrachial neurons (SPNs) receive peripheral nociceptive input, process it and transmit to the supraspinal centres. Although responses of SPNs to cutaneous receptive field stimulations have been intensively studied, the mechanisms of signal processing in these neurons are poorly understood. Therefore, we used an ex-vivo spinal cord preparation to examine synaptic and cellular mechanisms determining specific input-output characteristics of the neurons. The vast majority of the SPNs received a few direct nociceptive C-fiber inputs and generated one spike in response to saturating afferent stimulation, thus functioning as simple transducers of painful stimulus. However, 69% of afferent stimulation-induced action potentials in the entire SPN population originated from a small fraction (19%) of high-output neurons. These neurons received a larger number of direct Aδ- and C-fiber inputs, generated intrinsic bursts and efficiently integrated a local network activity via NMDA-receptor-dependent mechanisms. The high-output SPNs amplified and integrated the nociceptive input gradually encoding its intensity into the number of generated spikes. Thus, different mechanisms of signal processing allow lamina I SPNs to play distinct roles in nociception.

Differential cardiovascular responses to cutaneous afferent subtypes in a nociceptive intersegmental spinal reflex

Electrical stimulation to segmental dorsal cutaneous nerves (DCNs) activates a nociceptive sensorimotor reflex and the same afferent stimulation also evokes blood pressure (BP) and heart rate (HR) responses in rats. To investigate the relationship between those cardiovascular responses and the activation of nociceptive afferents, we analyzed BP and HR responses to electrical stimulations at each DCN from T6 to L1 at 0.5 mA to activate A-fiber alone or 5 mA to activate both A- and C-fibers at different frequencies. Evoked cardiovascular responses showed a decrease and then an increase in BP and an increase and then a plateau in HR. Segmentally, both cardiovascular responses tended to be larger when evoked from the more rostral DCNs. Stimulation frequency had a larger effect on cardiovascular responses than the rostrocaudal level of the DCN input. Stimulation strength showed a large effect on BP changes dependent on C-fibers whereas HR changes were dependent on A-fibers. Additional A-fiber activation by stimulating up to 4 adjacent DCNs concurrently, but only at 0.5 mA, affected HR but not BP. These data support that cutaneous nociceptive afferent subtypes preferentially contribute to different cardiovascular responses, A-fibers to HR and C-fibers to BP, with temporal (stimulation frequency) and spatial (rostrocaudal level) dynamics.