Orexin-1 receptor signaling within the lateral hypothalamus, but not bed nucleus of the stria terminalis, mediates context-induced relapse to alcohol seeking.

BACKGROUND: The lateral hypothalamic orexin (hypocretin) system has a well-established role in the motivation for reward. This has particular relevance to substance use disorders since orexin-1 receptors play a critical role in alcohol-seeking behavior, acting at multiple nodes in relapse-associated networks. AIMS: This study aimed to further our understanding of the role of orexin-1 receptor signaling within the lateral hypothalamus and bed nucleus of the stria terminalis, specifically in context-induced relapse to alcohol-seeking following punishment-imposed abstinence. METHODS: We trained inbred male alcohol-preferring rats to self-administer alcohol in one environment or context (Context A) and subsequently punished their alcohol-reinforced lever presses in a different environment (Context B) using contingent foot shock punishment. Finally, we tested rats for relapse-like behavior in either context following systemic, intra-lateral hypothalamus or intra-bed nucleus of the stria terminalis orexin-1 receptor antagonism with SB-334867. RESULTS/OUTCOMES: We found that systemic orexin-1 receptor antagonism significantly reduced alcohol-seeking in both contexts. Intra-lateral hypothalamus orexin-1 receptor antagonism significantly reduced alcohol-seeking in Context A whereas intra-bed nucleus of the stria terminalis orexin-1 receptor antagonism had no effect on alcohol-seeking behavior. CONCLUSIONS/INTERPRETATION: Our results suggest a role for the orexin-1 receptor system in context-induced relapse to alcohol-seeking. Specifically, intra-lateral hypothalamus orexin microcircuits contribute to alcohol-seeking.

Estradiol Acts in Lateral Thalamic Region to Attenuate Varicella Zoster Virus Associated Affective Pain.

Varicella zoster virus (VZV) results in chicken pox and herpes zoster. Female rats show a higher level of herpes zoster associated pain than males, consistent with human studies. In this study, we addressed the novel hypothesis that sex difference in herpes zoster associated pain is due, in part, to estradiol modulating activity in the thalamus. To test this hypothesis a high and low physiological dose of estradiol was administered to castrated and ovariectomized rats and the affective pain response was measured after injection of VZV into the whisker pad. Thalamic infusion of the estrogen receptor antagonist ICI 182,780 concomitant with a high dose of estradiol addressed the role of estradiol binding to its receptor to effect pain. Phosphorylated extracellular signal-regulated protein kinase (pERK) positive cells were measured in excitatory (glutaminase positive) and inhibitory (glutamate decarboxylase 67 positive) cells of the lateral thalamic region. Our results show that a high dose of estradiol significantly reduced the pain response in both males and females. pERK significantly increased in excitatory cells after treatment with a low dose of estradiol and increased in inhibitory cells after treatment with a high dose of estradiol. Administration of ICI 182,780 significantly increased the pain response, reduced expression of GABA related genes in the thalamic region and significantly reduced the number of inhibitory cells expressing pERK. The results suggest that estradiol attenuates herpes zoster pain by increasing the activity of inhibitory neurons within the thalamus and that this reduction includes an estrogen receptor dependent mechanism.

Electroacupuncture Treatment Alleviates the Remifentanil-Induced Hyperalgesia by Regulating the Activities of the Ventral Posterior Lateral Nucleus of the Thalamus Neurons in Rats.

Mechanisms underlying remifentanil- (RF-) induced hyperalgesia, a phenomenon that is generally named as opioid-induced hyperalgesia (OIH), still remain elusive. The ventral posterior lateral nucleus (VPL) of the thalamus, a key relay station for the transmission of nociceptive information to the cerebral cortex, is activated by RF infusion. Electroacupuncture (EA) is an effective method for the treatment of pain. This study aimed to explore the role of VPL in the development of OIH and the effect of EA treatment on OIH in rats. RF was administered to rats via the tail vein for OIH induction. Paw withdrawal threshold (PWT) in response to mechanical stimuli and paw withdrawal latency (PWL) to thermal stimulation were tested in rats for the assessment of mechanical allodynia and thermal hyperalgesia, respectively. Spontaneous neuronal activity and local field potential (LFP) in VPL were recorded in freely moving rats using the in vivo multichannel recording technique. EA at 2 Hz frequency (pulse width 0.6 ms, 1-3 mA) was applied to the bilateral acupoints "Zusanli" (ST.36) and "Sanyinjiao" (SP.6) in rats. The results showed that both the PWT and PWL were significantly decreased after RF infusion to rats. Meanwhile, both the spontaneous neuronal firing rate and the theta band oscillation in VPL LFP were increased on day 3 post-RF infusion, indicating that the VPL may promote the development of RF-induced hyperalgesia by regulating the pain-related cortical activity. Moreover, 2 Hz-EA reversed the RF-induced decrease both in PWT and PWL of rats and also abrogated the RF-induced augmentation of the spontaneous neuronal activity and the power spectral density (PSD) of the theta band oscillation in VPL LFP. These results suggested that 2 Hz-EA attenuates the remifentanil-induced hyperalgesia via reducing the excitability of VPL neurons and the low-frequency (theta band) oscillation in VPL LFP.

Stereotactic approach and electrophysiological characterization of thalamic reticular and dorsolateral nuclei of the juvenile pig.

Few reports exist on complex functions of pig's central nervous system. A direct access to thalamic structures enables a deeper understanding of neuronal networks. Here we present an easy to implement stereotactic approach to reach both reticular and dorsolateral thalamic nuclei (RTN and LD). In thirteen pigs (7 weeks old) the correct electrode position was confirmed for 22 out of 26 thalamic electrodes (RTN: A+2, L9, V24 and LD: A-2, L5, V20, with bregma A 0, L 0). Quantitative effects of isoflurane/nitrous oxide (State 1) and fentanyl sedation (State 2) were determined by brain hemodynamics and metabolism. Neurophysiologic features were performed by spectral power, coherence and SEP analysis. Brain blood flow (by 21 +/- 13%) and oxidative brain metabolism (CMRO, by 26 +/- 12%, CMRGlucose by 26 +/- 22%) were markedly reduced during State 1 (P<0.05). Regional thalamic blood flow exhibited similar alterations, but side-differences did not occur. State 1 induced quite similar brain activity in cortical as well as thalamic regions investigated. During State 2 electrocortical activity of low frequency ranges was markedly reduced, whereas spectral band power of high frequency ranges was additionally decreased in RTN (P<0.05). Thus, we used a convenient approach for targeted deep electrode implementation and characterized electrophysiological features in RTN and LD.

Transient attenuation of neuropathic manifestations in rats following lesion or reversible block of the lateral thalamic somatosensory nuclei.

BACKGROUND AND AIMS: Nociceptive behavior in animal models for mononeuropathy has been shown to be altered by spinal tract lesions which suggest a possible supraspinal modulation. The thalamus constitutes a chief center for the processing of nociception. We have, therefore, investigated the effects of transient or permanent blocks of the lateral somatosensory thalamic nuclei (the ventrobasal complex) on the neuropathic manifestations in rats. METHODS: Different groups of rats (n = 5-6) were subjected to mononeuropathy, following the spared nerve injury model, known to produce sustained heat hyperalgesia and tactile and cold allodynia which peaked about 2 weeks after nerve injury. This was followed by stereotaxic placement of either electrolytic or chemical lesions or implantation of mini osmotic pump for slow release of lidocaine in the ventrobasal complex. RESULTS: Chronic electrolytic and chemical lesions or reversible block of the lateral somatosensory thalamus produced transient (1-2 weeks) attenuation of neuropathic manifestations along with a persistent decrease of the hot plate latency. The most pronounced effect was observed on heat hyperalgesia, and the least significant and short-lived effect was observed on cold allodynia. CONCLUSION: We conclude that the lateral somatosensory thalamic complex is involved in the processing of neuropathic manifestations but cannot be considered as an obligatory or exclusive relay center for the neuropathic syndromes.

Differences between somatosensory-evoked potentials recorded from the ventral posterolateral thalamic nucleus, primary somatosensory cortex and vertex in the rat.

Somatosensory-evoked potential (SEP) components recorded over the primary somatosensory cortex (SI) and vertex in the rat within the 10-30 ms latency range were characterised with respect to the anatomy and function of the primary somatosensory pathway. To this aim, these components were compared to SEP components in the similar latency range recorded from the ventral posterolateral thalamic (VPL) nucleus, a nucleus known to be part of the subcortical structure of the primary somatosensory pathway and were described with respect to their stimulus-response characteristics and their response to the mu-opioid agonist fentanyl. The VPL positive (P)11-negative (N)18-P22 and SI P13-N18-P22 differed with respect to peak occurrence (P11 versus P13, respectively) and waveform morphology, but did not differ with respect to stimulus-response characteristics and their response to fentanyl. When compared to the vertex P15-N19-P26, the VPL P11-N18-P22 and SI P13-N18-P22 complex follow a relatively fast acquisition in stimulus intensity-response and were affected significantly less to increasing stimulus frequencies and to fentanyl. These results demonstrated that when compared to the VPL-SEP and SI-SEP, the Vx-SEP was modulated differently by the experimental conditions. It is suggested that this may be related to involvement of neural structures within different functional somatosensory pathways.

Microinjection of adrenomedullin into rostral ventrolateral medulla increases blood pressure, heart rate and renal sympathetic nerve activity in rats.

The present study was undertaken to examine the effects of microinjection of adrenomedullin (AM) into rostral ventrolateral medulla (RVLM) on mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in 34 anesthetized Sprague-Dawley rats. The results obtained are as follows. (1) Following microinjection of AM (10 micromol/L, 200 nl) into the RVLM, MAP, HR and RSNA were significantly increased from 99.09+/-3.32 mmHg, 370.78+/-7.84 bpm and 100+/-0% to 113.57+/-3.64 mmHg (P>0.001), 383.28+/-7.38 bpm (P>0.001) and 123.72+/-2.74% (P>0.001), respectively. (2) Pretreatment with microinjection of calcitonin gene-related peptide receptor antagonist CGRP8-37 (100 micromol/L, 200 nl) did not change the effects of AM. (3) L-arginine (100 mg/kg, 0.2 ml, i.v.), an NO precursor, abolished the effects of AM. This study demonstrates that AM acting at the rostral ventrolateral medulla may produce significant cardiovascular responses, the effects are not mediated by CGRP receptor but may be abolished by NO.

Muscarinic regulation of dendritic and axonal outputs of rat thalamic interneurons: a new cellular mechanism for uncoupling distal dendrites.

Inhibition is crucial for sharpening the sensory information relayed through the thalamus. To understand how the interneuron-mediated inhibition in the thalamus is regulated, we studied the muscarinic effects on interneurons in the lateral posterior nucleus and lateral geniculate nucleus of the thalamus. Here, we report that activation of muscarinic receptors switched the firing pattern in thalamic interneurons from bursting to tonic. Although neuromodulators switch the firing mode in several other types of neurons by altering their membrane potential, we found that activation of muscarinic subtype 2 receptors switched the fire mode in thalamic interneurons by selectively decreasing their input resistance. This is attributable to the muscarinic enhancement of a hyperpolarizing potassium conductance and two depolarizing cation conductances. The decrease in input resistance appeared to electrotonically uncouple the distal dendrites of thalamic interneurons, which effectively changed the inhibition pattern in thalamocortical cells. These results suggest a novel cellular mechanism for the cholinergic transformation of long-range, slow dendrite- and axon-originated inhibition into short-range, fast dendrite-originated inhibition in the thalamus observed in vivo. It is concluded that the electrotonic properties of the dendritic compartments of thalamic interneurons can be dynamically regulated by muscarinic activity.

[Preliminary study of analgesic mechanism of Buthus martensii Karsch (BmK) venom on central nervous system].

AIM: To investigate whether or not the lateral septal nucleus (LS) was one of important analgesic areas of BmK venom in the central nervous system (CNS), and, targeting on which receptor, analgesic effect was produced by it. METHODS: Pain threshold of skin was observed by the latent period of tail flick evoked by radiant heat. Glass micropipette placed in Pf was used to record unit discharges of neurons in it, before and after 0.01% BmK venom were injected into LS. Stainless steel cannula placed in the lateral cerebral ventricle (icy) and LS was used for microinjection. RESULTS: After injection of 2 microl 0.01% BmK venom into icy of rat, the pain threshold was apparently raised, which was completely returned by injection of 0.5 microl 0.25% naloxone into icy. After 0.5 microl 0.01% BmK venom was injected into LS, 71% (15/21) nociceptive-on neurons and 83.3% (5/6) nociceptive-off neurons decreased the nociceptive response to tail pinch, but no evident effect was observed in the non-nociceptive neurons. CONCLUSION: The analgesic effect of BmK venom was probably realized mainly by the opiate receptor, and LS was one of important analgesic areas of BmK venom on CNS.