Neuropsychiatric Behavioral Assessments in Mice After Acute and Long-Term Treatments of Low-Intensity Pulsed Ultrasound.

Introduction: To evaluate whether both acute and chronic low-intensity pulsed ultrasound (LIPUS) affect brain functions of healthy male and female mice. Methods: Ultrasound (frequency: 1.5 MHz; pulse: 1.0 kHz; spatial average temporal average (SATA) intensity: 25 mW/cm2; and pulse duty cycle: 20%) was applied at mouse head in acute test for 20 minutes, and in chronic experiment for consecutive 10 days, respectively. Behaviors were then evaluated. Results: Both acute and chronic LIPUS at 25 mW/cm2 exposure did not affect the abilities of movements, mating, social interaction, and anxiety-like behaviors in the male and female mice. However, physical restraint caused struggle-like behaviors and short-time memory deficits in chronic LIPUS groups in the male mice. Conclusion: LIPUS at 25 mW/cm2 itself does not affect brain functions, while physical restraint for LIPUS therapy elicits struggle-like behaviors in the male mice. An unbound helmet targeted with ultrasound intensity at 25-50 mW/cm2 is proposed for clinical brain disease therapy.

Increasing Pain Sensation Eliminates the Inhibitory Effect of Depression on Evoked Pain in Rats.

Although previous studies have suggested that depression may be associated with inhibition of evoked pain but facilitation of spontaneous pain, the mechanisms underlying these relationships are unclear. The present study investigated whether the difference between evoked and spontaneous pain on sensory (descending inhibition) and affective (avoidance motivation) components contributes to the divergent effects of depression on them. Depressive-like behavior was produced in male Wistar rats by unpredictable chronic mild stress (UCMS). Tone-laser conditioning and formalin-induced conditioned place avoidance (F-CPA) were used to explore avoidance motivation in evoked and spontaneous pain, respectively. Behavioral pharmacology experiments were conducted to examine descending inhibition of both evoked (thermal stimulation) and spontaneous pain behavior (formalin pain). The results revealed that the inhibitory effect of depression on evoked pain was eliminated following repeated thermal stimuli. Avoidance behavior in the tone-laser conditioning task was reduced in UCMS rats, relative to controls. However, avoidance motivation for formalin pain in the UCMS group was similar to controls. 5-HT1A receptor antagonism interfered with inhibition of pain responses over time. The present study demonstrated that the inhibitory effect of depression on evoked pain dissipates with increased nociception and that the sensory-discriminative and affective-motivational components of pain are jointly involved in the divergent effects of depression on pain.

Differential modulation of electrical stimulation of periaqueductal gray and thalamus on nociceptive behaviors of rats.

Deep brain stimulation (DBS) is a surgical treatment which has shown remarkable therapeutic benefits for patients with a variety of neurologic conditions. As an important application, DBS has been used to treat intractable pain for over 60 years. Clinical studies have revealed that the selection of the stimulation sites depended on the types of pain. In this study, we selected ventrolateral periaqueductal gray (vlPAG) and ventral posterior lateral nucleus (VPL) as the target brain areas, which were widely used in clinical treatment of refractory pain, to clarify and compare the effects of vlPAG and VPL stimulation on different models of pain. Acute pain was evoked by thermal stimulation. The chronic inflammatory pain was produced by complete Freund's adjuvant (CFA) injection, while neuropathic pain was induced by spinal nerve ligation (SNL) surgery. Some important results emerged from this study: (1) in the experiment of normal rats, we found that unilateral vlPAG stimulation could lead to a significant increase of the thermal withdrawal threshold in bilateral hindpaws of rats, which means a significant bilateral analgesic action; (2) in the CFA test, both contralateral vlPAG and VPL stimulation significantly alleviated the thermal hyperalgesia, which exhibited analgesic effects to the chronic inflammatory pain; (3) in the SNL experiment, the results revealed that contralateral VPL stimulation could significantly abolish the mechanical allodynia induced by SNL, indicating remarkable analgesic effect to neuropathic pain. But the vlPAG stimulation did not have any effect on the mechanical allodynia. These results suggest that the electrical stimulation of the PAG works more effectively on nociceptive pain, including acute pain and chronic inflammatory pain. Besides, the VPL stimulation is much more sensitive for chronic pain, including chronic inflammatory pain and neuropathic pain.

The effects of morphine on basal neuronal activities in the lateral and medial pain pathways.

Numerous studies indicate that morphine suppresses pain-evoked activities in both spinal and supraspinal regions. However, little is known about the effect of morphine on the basal brain activity in the absence of pain. The present study was designed to assess the effects of single-dose morphine on the spontaneous discharge of many simultaneously recorded single units, as well as their functional connections, in the lateral pain pathway, including the primary somatosensory cortex (SI) and ventral posterolateral thalamus (VPL), and medial pain pathway, including the anterior cingulate cortex (ACC) and medial dorsal thalamus (MD), in awake rats. Morphine (5mg/kg) was administered intraperitoneally before the recording. Naloxone plus morphine and normal saline injections were performed respectively as controls. The results showed that morphine administration produced significant changes in the spontaneous neuronal activity in more than one third of the total recorded neurons, with primary activation in the lateral pathway while both inhibition and activation in the medial pathway. Naloxone pretreatment completely blocked the effects induced by morphine. In addition, the correlated activities between and within both pain pathways was exclusively suppressed after morphine injection. These results suggest that morphine may play different roles in modulating neural activity in normal vs. pain states. Taken together, this is the first study investigating the morphine modulation of spontaneous neuronal activity within parallel pain pathways. It can be helpful for revealing neuronal population coding for the morphine action in the absence of pain, and shed light on the supraspinal mechanisms for preemptive analgesia.

The effect of depression on the thermal nociceptive thresholds in rats with spontaneous pain.

OBJECTIVE: Recently, there has been growing interest in the interaction between depressive disorders and pain. The purpose of this study was to examine whether depression would lead to a decreased sensitivity to noxious stimuli in rats with spontaneous pain. METHODS: The olfactory bulbectomized rats were used as a model of depression. The depression-like behaviors were assessed by open field test and changes in body weight. Formalin solution was injected into the rat hindpaw to produce ongoing pain. Noxious thermal stimuli were applied onto the hindpaw contralateral to formalin injection, and the withdrawal thresholds were measured. RESULTS: In non-depressive rats, the formalin-treated paw developed hypoalgesia to noxious stimuli while the contralateral paw was not affected. The depressive rats, however, showed a significantly lower sensitivity to noxious thermal stimulus, represented as higher withdrawal thresholds of the contralateral paw, when compared to the non-depressive rats. CONCLUSION: These results demonstrate that depression can alleviate the stimulus-evoked pain even in the context of formalin inflammatory pain, consistent with the previous clinical observations that patients suffering from both depression and persistent pain have decreased sensitivities to noxious experimental stimuli.