Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat.

Deep brain stimulation has been found to be effective in relieving intractable pain. The ventral tegmental area (VTA) plays a role not only in the reward process, but also in the modulation of nociception. Lesions of VTA result in increased pain thresholds and exacerbate pain in several pain models. It is hypothesized that direct activation of VTA will reduce pain experience. In this study, we investigated the effect of direct electrical stimulation of the VTA on mechanical, thermal and carrageenan-induced chemical nociceptive thresholds in Sprague-Dawley rats using our custom-designed wireless stimulator. We found that: (1) VTA stimulation itself did not show any change in mechanical or thermal threshold; and (2) the decreased mechanical and thermal thresholds induced by carrageenan injection in the hind paw contralateral to the stimulation site were significantly reversed by VTA stimulation. To further explore the underlying mechanism of VTA stimulation-induced analgesia, spinal cord dorsal horn neuronal responses to graded mechanical stimuli were recorded. VTA stimulation significantly inhibited dorsal horn neuronal activity in response to pressure and pinch from the paw, but not brush. This indicated that VTA stimulation may have exerted its analgesic effect via descending modulatory pain pathways, possibly through its connections with brain stem structures and cerebral cortex areas.

Cerebrovascular responses of the rat brain to noxious stimuli as examined by functional near-infrared whole brain imaging.

While near-infrared (NIR) spectroscopy has been increasingly used to detect stimulated brain activities with an advantage of dissociating regional oxy- and deoxyhemoglobin concentrations simultaneously, it has not been utilized much in pain research. Here, we investigated and demonstrated the feasibility of using this technique to obtain whole brain hemodynamics in rats and speculated on the functional relevance of the NIR-based hemodynamic signals during pain processing. NIR signals were emitted and collected using a 26-optodes array on rat's dorsal skull surface after the removal of skin. Following the subcutaneous injection of formalin (50 µl, 3%) into a hindpaw, several isolable brain regions showed hemodynamic changes, including the anterior cingulate cortex, primary/secondary somatosensory cortexes, thalamus, and periaqueductal gray (n = 6). Time courses of hemodynamic changes in respective regions matched with the well-documented biphasic excitatory response. Surprisingly, an atypical pattern (i.e., a decrease in oxyhemoglobin concentration with a concomitant increase in deoxyhemoglobin concentration) was seen in phase II. In a separate group of rats with innocuous brush and noxious pinch of the same area (n = 11), results confirmed that the atypical pattern occurred more likely in the presence of nociception than nonpainful stimulation, suggesting it as a physiological substrate when the brain processes pain. In conclusion, the NIR whole brain imaging provides a useful alternative to study pain in vivo using small-animal models. Our results support the notion that neurovascular response patterns depend on stimuli, bringing attention to the interpretation of vascular-based neuroimaging data in studies of pain.

Transcranial Focused Ultrasound Stimulation of Periaqueductal Gray for Analgesia.

OBJECTIVE: Transcranial focused ultrasound (tFUS) is regarded as a promising non-invasive stimulation tool for modulating brain circuits. The aim of this study is to explore the feasibility of tFUS stimulation for analgesia applications. METHODS: 50 µl of 3% formalin solution was injected into the rat's left hindpaw to build a pain model, and then the local field potential (LFP) activities of the dorsal horn were tracked after a recording electrode was placed in the spinal cord. Rats were randomly divided into two groups: control group and tFUS group. At the 30th minute after formalin injection, tFUS (US-650 kHz, PD = 1 ms, PRF = 100 Hz, 691 mW/cm2) was conducted to stimulate the periaqueductal gray (PAG) for 5 minutes (on 5 s and off 5 s) in the tFUS group, but there was no treatment in the control group. In addition, the analgesia mechanism (LFP recording from the PAG) and safety assessment (histology analysis) were carried out. RESULTS: The tFUS stimulation of the PAG can suppress effectively the nociceptive activity generated by formalin. The findings of the underlying mechanism exploration indicated that the tFUS stimulation was able to activate the PAG directly without causing notable temperature change and tissue injury. CONCLUSION: The results illustrated that the tFUS stimulation of the PAG can achieve the effect of analgesia. SIGNIFICANCE: This work provides new insights into the development of non-invasive analgesic technology in the future.

Piezoelectric ultrasound energy-harvesting device for deep brain stimulation and analgesia applications.

Supplying wireless power is a challenging technical problem of great importance for implantable biomedical devices. Here, we introduce a novel implantable piezoelectric ultrasound energy-harvesting device based on Sm-doped Pb(Mg1/3Nb2/3)O3-PbTiO3 (Sm-PMN-PT) single crystal. The output power density of this device can reach up to 1.1 W/cm2 in vitro, which is 18 times higher than the previous record (60 mW/cm2). After being implanted in the rat brain, under 1-MHz ultrasound with a safe intensity of 212 mW/cm2, the as-developed device can produce an instantaneous effective output power of 280 µW, which can immediately activate the periaqueductal gray brain area. The rat electrophysiological experiments under anesthesia and behavioral experiments demonstrate that our wireless-powered device is well qualified for deep brain stimulation and analgesia applications. These encouraging results provide new insights into the development of implantable devices in the future.

Quantification of light reflectance spectroscopy and its application: determination of hemodynamics on the rat spinal cord and brain induced by electrical stimulation.

Two quantification methods for light reflectance spectroscopy (LRS) were developed and validated to determine absolute and relative values of hemodynamic parameters and light scattering, followed by a specific application using in vivo animal experiments. A single-channel LRS system consisted of a light source, CCD-array detector, and a computer along with a bifurcated, 2-mm-diameter optical probe; this system was utilized to perform laboratory tissue phantoms for validation of the algorithms. In the animal study, a multi-channel, multisite approach was used to measure several reflectance spectra from rat brain and spinal cord on both the ipsi-lateral and contra-lateral sides, using thin 800-µm-diameter optic probes. The neuro-hemodynamic changes were induced by 10-V electrical stimulation in rat hind paw. The LRS data of the animals were analyzed using both absolute and relative methods. The results show that the relative method is computation-efficient and offers a quick estimation of changes in oxy-hemoglobin concentration for real-time monitoring. The absolute quantification method, on the other hand, provides us with an accurate computational tool to calculate absolute values of oxy-, deoxy-, total hemoglobin concentrations, and light scattering coefficients. We also observe that the hemodynamic responses in rat spinal cord were delayed with a few seconds and have an overall broader full width at half maximum, as compared to those from rat somatosensory cortex. LRS as a measurement system provides a robust method for studying local hemodynamic changes and a potential technique to investigate hemo-neural mechanisms in pain processing.

The biopsychosocial approach to chronic pain: scientific advances and future directions.

The prevalence and cost of chronic pain is a major physical and mental health care problem in the United States today. As a result, there has been a recent explosion of research on chronic pain, with significant advances in better understanding its etiology, assessment, and treatment. The purpose of the present article is to provide a review of the most noteworthy developments in the field. The biopsychosocial model is now widely accepted as the most heuristic approach to chronic pain. With this model in mind, a review of the basic neuroscience processes of pain (the bio part of biopsychosocial), as well as the psychosocial factors, is presented. This spans research on how psychological and social factors can interact with brain processes to influence health and illness as well as on the development of new technologies, such as brain imaging, that provide new insights into brain-pain mechanisms.

Opioid tapering in patients with prescription opioid use disorder: A retrospective study.

BACKGROUND AND AIMS: Opioid use disorder (OUD) refers to a maladaptive pattern of opioid use leading to clinically significant impairment or distress. OUD causes, and vice versa, misuses and abuse of opioid medications. Clinicians face daily challenges to treat patients with prescription opioid use disorder. An evidence-based management for people who are already addicted to opioids has been identified as the national priority in the US; however, options are limited in clinical practices. In this study, we aimed to explore the success rate and important adjuvant medications in the medication assisted treatment with temporary use of methadone for opioid discontinuation in patients with prescription OUD. METHODS: This is a retrospective chart review performed at a private physician office for physical medicine and rehabilitation. We reviewed all medical records dated between December 1st, 2011 and August 30th, 2016. The initial evaluation of the included patients (N=140) was completed between December 1st, 2011 and December 31st, 2014. They all have concumittant prescription OUD and chronic non-cancer pain. The patients (87 female and 53 male) were 46.7±12.7 years old, and had a history of opioid use of 7.7±6.1 years. All patients received the comprehensive opioid taper treatments (including interventional pain management techniques, psychotherapy, acupuncture, physical modalities and exercises, and adjuvant medications) on top of the medication assisted treatment using methadone (transient use). Opioid tapering was considered successful when no opioid medication was used in the last patient visit. RESULTS: The 140 patients had pain of 9.6±8.4 years with 8/10 intensity before treatment which decreased after treatment in all comparisons (p<0.001 for all). Opioids were successfully tapered off in 39 (27.9%) patients after 6.6±6.7 visits over 8.8±7.2 months; these patients maintained opioid abstinence over 14.3±13.0 months with regular office visits. Among the 101 patients with unsuccessful opioid tapering, 13 patients only visited the outpatient clinic once. Significant differences were found between patients with and without successful opioid tapering in treatment duration, number of clinic visits, the use of mirtazepine, bupropion, topiramate, and trigger point injections with the univariate analyses. The use of mirtazepine (OR, 3.75; 95% CI, 1.48-9.49), topiramate (OR, 5.61; 95% CI, 1.91-16.48), or bupropion (OR, 2.5; 95% CI, 1.08-5.81) was significantly associated with successful opioid tapering. The associations remain significant for mirtazepine and topiramate (not bupropion) in different adjusted models. CONCLUSIONS: With comprehensive treatments, 27.9% of patients had successful opioid tapering with opioid abstinence for over a year. The use of mirtazepine, topiramate, or likely bupropion was associated with successful opioid tapering in the medication assisted treatment with temporary use of methadone. Opioid tapering may be a practical option and should be considered for managing prescription OUD. IMPLICATIONS: For patients with OUD, indefinite opioid maintenance treatment may not be necessary. Considering the ethical values of autonomy, nonmaleficence, and beneficence, clinicians should provide patients with OUD the option of opioid tapering.

Determination of hemoglobin oxygen saturation in rat sciatic nerve by in vivo near infrared spectroscopy.

The purpose of this study is to investigate the values of hemoglobin oxygen saturation in the sciatic nerve of the rat following spinal nerve ligation. An optical spectroscopic technique along with a fiber optic probe was used to test the hypothesis that demyelination and degeneration after nerve injury lead to a significant decrease in the percentage of hemoglobin oxygen saturation. A modified spinal nerve ligation method was used to induce the degeneration, and three types of ligation on left spinal nerve (L4, L4 and L5, L5) were performed in rats. The optical reflectance measurements were taken from the left and right sciatic nerves on postoperative days 1, 4, 7, and 14. No significant difference was found among the three types of ligation, nor was between left and right sciatic nerve at postoperative day 1. Significant decreases in oxygen saturation percentages were found between left and right sciatic nerves at postoperative days 4, 7, and 14. This study continues to show the effectiveness of optical methods in determining/differentiating tissue properties, providing an excellent and robust in vivo technique that can have a potential clinical application in detecting demyelination and degeneration of the nervous system.

Reduced local field potential power in the medial prefrontal cortex by noxious stimuli.

Nociceptive signals produced by noxious stimuli at the periphery reach the brain through ascending pathways. These signals are processed by various brain areas and lead to activity changes in those areas. The medial prefrontal cortex (mPFC) is involved in higher cognitive functions and emotional processing. It receives projections from brain areas involved in nociception. In this study, we investigated how nociceptive input from the periphery changes the local field potential (LFP) activity in the mPFC. Three different types of noxious stimuli were applied to the hind paw contralateral to the LFP recording site. They were transcutaneous electrical stimulations, mechanical stimuli and a chemical stimulus (formalin injection). High intensity transcutaneous stimulations (10V to 50V) and noxious mechanical stimulus (pinch) significantly reduced the LFP power during the stimulating period (p<0.05), but not the low intensity subcutaneous stimulations (0.1V to 5V) and other innocuous mechanical stimuli (brush and pressure). More frequency bands were inhibited with increased intensity of transcutaneous electrical stimulation, and almost all frequency bands were inhibited by stimulations at or higher than 30v. Pinch significantly reduced the power for beta band and formalin injection significantly reduced the power of alpha and beta band. Our data demonstrated the noxious stimuli-induced reduction of LFP power in the mPFC, which indicates the active processing of nociceptive information by the mPFC.

Light scattering from rat nervous system measured intraoperatively by near-infrared reflectance spectroscopy.

Our goal is to quantify scattering properties of near-IR light in the rat spinal cord region and to differentiate healthy and demyelinated peripheral nerves intraoperatively based on differential light scattering. For the rat spinal cord, optical reflectance is measured from the spinal cord surface at spatial intervals of 1 mm using a needle probe. Data are acquired from left and right lumbar regions of the animals as well as on the central blood vessels. The reduced scattering coefficient mu(s)' is found to be higher (34.2+/-2.1 cm(-1)) in the lumbar regions of the spinal cord than on the central blood vessel (19.9+/-1.0 cm(-1)). This methodology is extended to detect differences in the rat sciatic nerves following left L4 spinal nerve ligation. The reflectance is taken at the same five regions at postoperative days 1, 4, 7, and 14. Significant differences are seen in both the spectral slope and mu(s)' values on postoperative days 4, 7, and 14, indicating that either of the two quantities could be used as a marker for demyelination. We prove the usefulness of the technique, which may have a possible clinical application for minimally invasive, intraoperative diagnosis and monitoring of demyelination diseases, such as multiple sclerosis in the central nervous system or degeneration of the peripheral nervous system.

Detection of degeneration in rat sciatic nerve by in vivo near infrared spectroscopy.

We have recently developed an optical spectroscopy technique to monitor light scattering changes of the nervous system in vivo. Near infrared (NIR) spectroscopy emphasizes the detection of light scattering properties, which are prominent within the wavelength range of 700 to 850 nm wavelength. The purpose of this study is to test the hypothesis that demyelination and degeneration of the sciatic nerves after nerve injury will lead to a change in light scattering properties and be detected by the NIR technique. Left spinal nerve ligations (L4, L4 and L5, L5) were performed in rats. The scattering properties of the left (ligated) and right (control) sciatic nerve were measured by the NIR reflectance using a bifurcated needle probe at postoperative days 1, 4, 7, and 14. The results show that there was no significant difference among three types of ligation, and neither did the readings between left and right sciatic nerve at postoperative day 1. Significant decreases in light scattering indexes were found between left and right sciatic nerves at postoperative days 4, 7, and 14. It is concluded that our initial hypothesis is proven, suggesting that the NIR technique may have a potential for clinical application in detecting demyelination and degeneration of the nervous system.

Hemodynamic and Light-Scattering Changes of Rat Spinal Cord and Primary Somatosensory Cortex in Response to Innocuous and Noxious Stimuli.

Neuroimaging technologies with an exceptional spatial resolution and noninvasiveness have become a powerful tool for assessing neural activity in both animals and humans. However, the effectiveness of neuroimaging for pain remains unclear partly because the neurovascular coupling during pain processing is not completely characterized. Our current work aims to unravel patterns of neurovascular parameters in pain processing. A novel fiber-optic method was used to acquire absolute values of regional oxy- (HbO) and deoxy-hemoglobin concentrations, oxygen saturation rates (SO2), and the light-scattering coefficients from the spinal cord and primary somatosensory cortex (SI) in 10 rats. Brief mechanical and electrical stimuli (ranging from innocuous to noxious intensities) as well as a long-lasting noxious stimulus (formalin injection) were applied to the hindlimb under pentobarbital anesthesia. Interhemispheric comparisons in the spinal cord and SI were used to confirm functional activation during sensory processing. We found that all neurovascular parameters showed stimulation-induced changes; however, patterns of changes varied with regions and stimuli. Particularly, transient increases in HbO and SO2 were more reliably attributed to brief stimuli, whereas a sustained decrease in SO2 was more reliably attributed to formalin. Only the ipsilateral SI showed delayed responses to brief stimuli. In conclusion, innocuous and noxious stimuli induced significant neurovascular responses at critical centers (e.g., the spinal cord and SI) along the somatosensory pathway; however, there was no single response pattern (as measured by amplitude, duration, lateralization, decrease or increase) that was able to consistently differentiate noxious stimuli. Our results strongly suggested that the neurovascular response patterns differ between brief and long-lasting noxious stimuli, and can also differ between the spinal cord and SI. Therefore, a use of multiple-parameter strategy tailored by stimulus modality (brief or long-lasting) as well as region-dependent characteristics may be more effective in detecting pain using neuroimaging technologies.

The Scalp Confounds Near-Infrared Signal from Rat Brain Following Innocuous and Noxious Stimulation.

Functional near-infrared imaging (fNIRI) is a non-invasive, low-cost and highly portable technique for assessing brain activity and functions. Both clinical and experimental evidence suggest that fNIRI is able to assess brain activity at associated regions during pain processing, indicating a strong possibility of using fNIRI-derived brain activity pattern as a biomarker for pain. However, it remains unclear how, especially in small animals, the scalp influences fNIRI signal in pain processing. Previously, we have shown that the use of a multi-channel system improves the spatial resolution of fNIRI in rats (without the scalp) during pain processing. Our current work is to investigate a scalp effect by comparing with new data from rats with the scalp during innocuous or noxious stimulation (n = 6). Results showed remarkable stimulus-dependent differences between the no-scalp and intact-scalp groups. In conclusion, the scalp confounded the fNIRI signal in pain processing likely via an autonomic mechanism; the scalp effect should be a critical factor in image reconstruction and data interpretation.

Periaqueductal gray-evoked dorsal root reflex is frequency dependent.

The dorsal root reflex (DRR) is an antidromic action potential originating in the spinal cord that propagates toward the periphery. Given that both GABA(A) and 5-HT(3) receptors are involved in the generation of DRRs and stimulation of the periaqueductal gray (PAG) can induce the release of GABA and serotonin within the spinal cord, we investigated the modulation of DRRs by the PAG descending system. The central end of the cut left L5 dorsal root in adult Sprague-Dawley rats was tested with single fiber recording. Stimulating electrodes were placed in the PAG, sciatic nerve, or transcutaneously across hindpaws. Fifty-seven DRRs were recorded for the effect of PAG stimulation in 19 rats, and 51 DRRs from 26 rats and nine DRRs from seven rats were recorded for an effect of ipsilateral and contralateral peripheral stimulation, respectively. The results were expressed as a percentage of the number of DRRs over the number of stimuli. PAG stimulation at 0.2, 0.5, 5, 20, and 50 Hz produced ratio's of 113.16+/-9.84, 114.54+/-12.22, 24.6+/-3.23, 17.77+/-4.76, and 12.62+/-3.44 (%), respectively. Stimulation at ipsilateral peripheral nerve evoked DRRs of 103.26+/-8.93, 95.27+/-10.57, 37.66+/-7.55, 11.32+/-4.96, and 5.32+/-3.82 (%), respectively. Stimulation of the contralateral peripheral nerve evoked DRRs of 90.88+/-15.59, 44.30+/-10.77, 6.29+/-1.63, 0.45+/-0.19, and 0.29+/-0.15 (%), respectively. Transection at the thoracic spinal level completely eliminated PAG-induced DRRs. In conclusion, both PAG and peripheral stimulation produced DRRs in a frequency dependent manner. Stimulus intensity has no significant effect on DRRs.

The anterior cingulate cortex and pain processing.

The neural network that contributes to the suffering which accompanies persistent pain states involves a number of brain regions. Of primary interest is the contribution of the cingulate cortex in processing the affective component of pain. The purpose of this review is to summarize recent data obtained using novel behavioral paradigms in animals based on measuring escape and/or avoidance of a noxious stimulus. These paradigms have successfully been used to study the nature of the neuroanatomical and neurochemical contributions of the anterior cingulate cortex (ACC) to higher order pain processing in rodents.

Simultaneous absolute measures of glabrous skin hemodynamic and light-scattering change in response to formalin injection in rats.

Subcutaneous injection of formalin is a well-known model to study the nature of inflammatory pain. One of the cardinal signs of inflammation is redness, as a result of increased blood perfusion. We used an optical technology, light reflectance spectroscopy, to noninvasively obtain absolute measures of cutaneous hemodynamic components, including the concentrations of oxy- ([HbO]), deoxy- ([Hb]), total-hemoglobin ([HbT]), oxygen saturation (SO(2)), and the reduced light-scattering coefficient (µs'). The objective is to assess the effect of formalin-induced skin inflammation on the aforementioned parameters. Six rats were injected with formalin (50 µl, 3%) into left hind paw under pentobarbital anesthesia. Our results indicate prolonged increases in [HbO], [HbT], and SO(2) post injection only in the ipsilateral side. No statistically significant changes in [Hb] and µ(s)' occurred in either side. The arterial blood influx tends to be the major attribute of local hyperemia during inflammation. Thereby, [HbO] appears to be superior to [Hb] in measuring inflammation. In conclusion, the needle-probe-based light reflectance can be a feasible means to obtaining absolute measures of skin hemodynamic and light-scattering parameters when studying inflammatory pain.

Septal stimulation inhibits spinal cord dorsal horn neuronal activity.

Deep brain stimulation (DBS) has been used for relieving chronic pain in patients that have been through other existing options. The septum has been one of the targets for such treatment. The purpose of this study was to determine the inhibitory effect of electrical stimulation in the medial septum diagonal band of broca (MSDB) on neuronal activity in the spinal cord of rats anesthetized with sodium pentobarbital. While unilaterally stimulating the MSDB, wide dynamic range neurons in the lumbar region of the spinal cord were recorded in response to graded mechanical stimulation of the hind paws (brush, pressure, and pinch). Stimulation was at 1, 5, 10, and 20V, at 100Hz, and 0.1ms duration. Significant bilateral reduction was observed in response to pressure (ipsilaterally: 0.90±0.05, 0.48±0.06*, 0.55±0.05*, 0.40±0.05*; and contralaterally: 0.70±0.06*, 0.59±0.08*, 0.75±0.05*, 0.49±0.07*) and pinch (ipsilaterally: 0.89±0.08, 0.46±0.05*, 0.54±0.04*, 0.50±0.05*; and contralaterally: 0.78±0.05, 0.61±0.07*, 0.64±0.04*, 0.53±0.06*). Data were expressed as a fraction of control. Significant changes were also found in responses to brush in certain groups (ipsilaterally: 1.08±0.08, 0.72±0.06*, 1.00±0.12, 0.65±0.06*; and contralaterally: 0.93±0.05, 0.77±0.07*, 0.98±0.05, 0.84±0.07). Further analysis suggested that 5V was adequate for achieving optimal inhibition. It is concluded that the MSDB can be used as alternative target for DBS in the treatment of pain.

Biphasic effects of the anterior cingulate cortex stimulation on glabrous skin blood flow in rats.

A growing body of evidence indicates that the anterior cingulate cortex (ACC) is associated with sensory, cognition and emotion processing. We have shown that electrical stimulation of rat ACC depressed the spinal cord dorsal horn neuron activity in response to noxious stimuli, possibly through a release of GABA. GABA may elicit dorsal root reflexes (DRRs) to induce peripheral vasodilatation. On the other hand, the ACC may also regulate autonomic flow via the lateral hypothalamus (LH). The goal of this work was to investigate the role of ACC in regulating autonomic activity. A laser Doppler imager was used to continuously monitor rat glabrous skin blood perfusion in both hind paws, while a simultaneous heart rate (HR) and DRRs were recorded to assess contributions of sympathetic flow and sensory afferent to the ACC-induced vascular change. Twenty-three rats were divided into three groups: a unilateral electrolytic LH lesion group (n = 6), a sham lesion group (n = 9), and a control group (neither lesion nor stimulation, n = 8). ACC stimulation induced a biphasic systemic vascular response, with an initial transient cutaneous vasoconstriction followed by a prolonged vasodilatation. Unilateral LH lesion did not alter this biphasic response. A short-term tachycardia occurred in response to the ACC stimulation, but did not correlate with the prolonged vasodilatation. No significant change in DRRs was found (in 35 fibers). ACC stimulation induced a biphasic vascular response in the skin. Data are consistent with sympathetic contribution. However, other mechanisms should also be involved.

Near infrared and visible spectroscopic measurements to detect changes in light scattering and hemoglobin oxygen saturation from rat spinal cord during peripheral stimulation.

In this study, we investigated dynamic changes in light scattering and hemoglobin oxygen saturation (S(sc)O(2)) on the rat spinal cord due to peripheral electrical stimulation by measuring near infrared (NIR) and visible spectroscopy, respectively. The spectral slope in the wavelength region between 700 and 900 nm is used as an index (S(NIR)) to quantify light scattering. With a 100-mum (source-detector separation) fiber-optic needle probe, optical reflectance was measured from the left lumbar region, specifically LL5, of the spinal cord surface at a height of 575 mum from the spinal cord surface. Graded electrical stimulations from 20 to 50 V, in increments of 10 V, were given to the plantar surface of the rat left hind paw for a period of 20 s. Changes in both light scattering (S(NIR)) and S(sc)O(2) were determined as a difference between the baseline and the maximum of slope value and hemoglobin oxygen saturation, respectively, during the stimulation period. There were significant differences in both S(NIR) and S(sc)O(2) during stimulation, with the average percentage changes of 10.9% and 15.5%, respectively. We observed that both S(NIR) and S(sc)O(2) measured at the spinal cord are insensitive to the intensity of the electrical stimulus, which is possibly caused by the nonlinear process of neurovascular coupling. Our finding essentially indicates that peripheral electrical stimulation results in significant changes in both light scattering and hemoglobin oxygen saturation on the rat spinal cord, and ignoring light scattering changes could lead to possible negative offsets of hemodynamic parameters (oxy-, deoxy-, and total hemoglobin concentrations) obtained in the functional optical imaging in the brain.

Selective regulation of pain affect following activation of the opioid anterior cingulate cortex system.

Morphine and surgical cingulotomy, or transection of the anterior cingulate cortex (ACC), provides relief of chronic pain by selectively decreasing the affective dimension of the condition without altering sensory processing. Clinical reports suggest that morphine might be acting at the level of the ACC to alter the complex experience of pain. Therefore, the purpose of this experiment was to directly examine the functional role of the ACC in processing the aversive nature of pain induced by ligation of the L5 spinal nerve. Systemic administration of low dose morphine produced a selective attenuation of pain affect, as indicated by a decrease in the aversiveness of noxious cutaneous stimulation in nerve-damaged animals, with no alteration of mechanical paw withdrawal threshold. Supraspinally, microinjection of morphine into the ACC produced a selective naloxone reversible reduction in pain affect, as indicated by a decrease in the aversiveness of noxious cutaneous stimulation in nerve-damaged animals, with no alteration of response to mechanical stimulation. These data demonstrate the central role of the ACC opioid system in selectively processing the aversive quality of noxious mechanical stimulation in animals with a persistent pain condition.