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Rationale: In utero opioid exposure is associated with lower weight and a neonatal opioid withdrawal syndrome (NOWS) at birth, along with longer-term adverse neurodevelopmental outcomes and mood disorders. While NOWS is sometimes treated with continued opioids, clinical studies have not addressed if long-term neurobehavioral outcomes are worsened with continued postnatal exposure to opioids. In addition, pre-clinical studies comparing in utero only opioid exposure to continued post-natal opioid administration for withdrawal mitigation are lacking. Objectives: Here, we sought to understand the impact of continued postnatal opioid exposure on long term behavioral consequences. Methods: We implemented a rodent perinatal opioid exposure model of oxycodone (Oxy) exposure that included Oxy exposure until birth (short Oxy) and continued postnatal opioid exposure (long Oxy) spanning gestation through birth and lactation. Results: Short Oxy exposure was associated with a sex-specific increase in weight gain trajectory in adult male mice. Long Oxy exposure caused an increased weight gain trajectory in adult males and alterations in nociceptive processing in females. Importantly, there was no evidence of long-term social behavioral deficits, anxiety, hyperactivity, or memory deficits following short or long Oxy exposure. Conclusions: Our findings suggest that offspring with prolonged opioid exposure experienced some long-term sequelae compared to pups with opioid cessation at birth. These results highlight the potential long-term consequences of opioid administration as a mitigation strategy for clinical NOWS symptomology and suggest alternatives should be explored. [ABSTRACT FROM AUTHOR]

Pain treatment services and clinical indicators of pain chronicity focus on afferent nociceptive projections and psychological markers of pain perception with little focus on motor processes. Research supports a strong role for the motor system both in terms of pain related disability and in descending pain modulation. However, there is little understanding of the neurological regions implicated in pain-motor interactions and how the motor and sensory systems interact under conditions of pain. We performed an ALE meta-analysis on two clinical cohorts with atypical sensory and motor processes under conditions of pain and no pain. Persons with sensory altered processing (SAP) and no pain presented with greater activity in the precentral and supplementary motor area relative to persons with self-reported pain. In persons with motor altered processing (MAP), there appeared to be a suppression of activity in key pain regions such as the insula, thalamus, and postcentral gyrus. As such, activation within the motor system may play a critical role in dampening pain symptoms in persons with SAP, and in suppressing activity in key pain regions of the brain in persons with MAP. Future research endeavors should focus on understanding how sensory and motor processes interact both to understand disability and discover new treatment avenues. [ABSTRACT FROM AUTHOR]

Recent studies have established the presence of nociceptive steady-state evoked potentials (SSEPs), generated in response to thermal or intra-epidermal electric stimuli. This study explores cortical sources and generation mechanisms of nociceptive SSEPs in response to intra-epidermal electric stimuli. Our method was to stimulate healthy volunteers (n = 22, all men) with 100 intra-epidermal pulse sequences. Each sequence had a duration of 8.5 s, and consisted of pulses with a pulse rate between 20 and 200 Hz, which was frequency modulated with a multisine waveform of 3, 7 and 13 Hz (n = 10, 1 excluded) or 3 and 7 Hz (n = 12, 1 excluded). As a result, evoked potentials in response to stimulation onset and contralateral SSEPs at 3 and 7 Hz were observed. The SSEPs at 3 and 7 Hz had an average time delay of 137 ms and 143 ms respectively. The evoked potential in response to stimulation onset had a contralateral minimum (N1) at 115 ms and a central maximum (P2) at 300 ms. Sources for the multisine SSEP at 3 and 7 Hz were found through beamforming near the primary and secondary somatosensory cortex. Sources for the N1 were found near the primary and secondary somatosensory cortex. Sources for the N2-P2 were found near the supplementary motor area. Harmonic and intermodulation frequencies in the SSEP power spectrum remained below a detectable level and no evidence for nonlinearity of nociceptive processing, i.e. processing of peripheral firing rate into cortical evoked potentials, was found. [ABSTRACT FROM AUTHOR]

Sleep deprivation has been shown to increase pain intensity and decrease pain thresholds in healthy subjects. In chronic pain patients, sleep impairment often worsens the perceived pain intensity. This increased pain perception is the result of altered nociceptive processing. We recently developed a method to quantify and monitor altered nociceptive processing by simultaneous tracking of psychophysical detection thresholds and recording of evoked cortical potentials during intra-epidermal electric stimulation. In this study, we assessed the sensitivity of nociceptive detection thresholds and evoked potentials to altered nociceptive processing after sleep deprivation in an exploratory study with 24 healthy male and 24 healthy female subjects. In each subject, we tracked nociceptive detection thresholds and recorded central evoked potentials in response to 180 single- and 180 double-pulse intra-epidermal electric stimuli. Results showed that the detection thresholds for single- and double-pulse stimuli and the average central evoked potential for single-pulse stimuli were significantly decreased after sleep deprivation. When analyzed separated by sex, these effects were only significant in the male population. Multivariate analysis showed that the decrease of central evoked potential was associated with a decrease of task-related evoked activity. Measurement repetition led to a decrease of the detection threshold to double-pulse stimuli in the mixed and the female population, but did not significantly affect any other outcome measures. These results suggest that simultaneous tracking of psychophysical detection thresholds and evoked potentials is a useful method to observe altered nociceptive processing after sleep deprivation, but is also sensitive to sex differences and measurement repetition. [ABSTRACT FROM AUTHOR]

Background. Recently, event-related potentials (ERPs) evoked by skin puncture, commonly used for blood sampling, have received attention as a pain assessment tool in neonates. However, their latency appears to be far shorter than the latency of ERPs evoked by intraepidermal electrical stimulation (IES), which selectively activates nociceptive A and C fibers. To clarify this important issue, we examined whether ERPs evoked by skin puncture appropriately reflect central nociceptive processing, as is the case with IES. Methods. In Experiment 1, we recorded evoked potentials to the click sound produced by a lance device (click-only), lance stimulation with the click sound (click+lance), or lance stimulation with white noise (WN+lance) in eight healthy adults to investigate the effect of the click sound on the ERP evoked by skin puncture. In Experiment 2, we tested 18 heathy adults and recorded evoked potentials to shallow lance stimulation (SL) with a blade that did not reach the dermis (0.1mminsertion depth); normal lance stimulation (CL) (1 mm depth); transcutaneous electrical stimulation (ES), which mainly activates A fibers; and IES, which selectively activates A fibers when low stimulation current intensities are applied. White noise was continuously presented during the experiments. The stimulations were applied to the hand dorsum. In the SL, the lance device did not touch the skin and the blade was inserted to a depth of 0.1mminto the epidermis, where the free nerve endings of A fibers are located, which minimized the tactile sensation caused by the device touching the skin and the activation of A fibers by the blade reaching the dermis. In the CL, as in clinical use, the lance device touched the skin and the blade reached a depth of 1 mm from the skin surface, i.e., the depth of the dermis at which the A fibers are located. Results. The ERP N2 latencies for click-only (122 2.9 ms) and click+lance (121 6.5 ms) were significantly shorter than that for WN+lance (154 7.1 ms). The ERP P2 latency for click-only (191 11.3 ms) was significantly shorter than those for click+lance (249 18.6 ms) and WN+lance (253 11.2 ms). This suggests that the click sound shortens the N2 latency of the ERP evoked by skin puncture. The ERP N2 latencies for SL, CL, ES, and IES were 146 8.3, 149 9.9, 148 13.1, and 197 21.2 ms, respectively. The ERP P2 latencies were 250 18.2, 251 14.1, 237 26.3, and 294 30.0 ms, respectively. The ERP latency for SL was significantly shorter than that for IES and was similar to that for ES. This suggests that the penetration force generated by the blade of the lance device activates the A fibers, consequently shortening the ERP latency. Conclusions. Lance ERP may reflect the activation of A fibers rather than A fibers. A pain index that correctly and reliably reflects nociceptive processing must be developed to improve pain assessment and management in neonates. [ABSTRACT FROM AUTHOR]

Monitoring nociceptive processing is a current challenge due to a lack of objective measures. Recently, we developed a method for simultaneous tracking of psychophysical detection probability and brain evoked potentials in response to intra-epidermal stimulation. An exploratory investigation showed that we could quantify nociceptive system behavior by estimating the effect of stimulus properties on the evoked potential (EP). The goal in this work was to accurately measure nociceptive system behavior using this method in a large group of healthy subjects to identify the locations and latencies of EP components and the effect of single- and double-pulse stimuli with an inter-pulse interval of 10 or 40 ms on these EP components and detection probability. First, we observed the effect of filter settings and channel selection on the EP. Subsequently, we compared statistical models to assess correlation of EP and detection probability with stimulus properties, and quantified the effect of stimulus properties on both outcome measures through linear mixed regression. We observed lateral and central EP components in response to intra-epidermal stimulation. Detection probability and central EP components were positively correlated to the amplitude of each pulse, regardless of the inter-pulse interval, and negatively correlated to the trial number. Both central and lateral EP components also showed strong correlation with detection. These results show that both the observed EP and the detection probability reflect the various steps of processing of a nociceptive stimulus, including peripheral nerve fiber recruitment, central synaptic summation, and habituation to a repeated stimulus. [ABSTRACT FROM AUTHOR]

Measuring altered nociceptive processing involved in chronic pain is difficult due to a lack of objective methods. Potential methods to characterize human nociceptive processing involve measuring neurophysiological activity and psychophysical responses to well-defined stimuli. To reliably measure neurophysiological activity in response to nociceptive stimulation using EEG, synchronized activation of nerve fibers and a large number of stimuli are required. On the other hand, to reliably measure psychophysical detection thresholds, selection of stimulus amplitudes around the detection threshold and many stimulus–response pairs are required. Combining the two techniques helps in quantifying the properties of nociceptive processing related to detected and non-detected stimuli around the detection threshold. The two techniques were combined in an experiment including 20 healthy participants to study the effect of intra-epidermal electrical stimulus properties (i.e. amplitude, single- or double-pulse and trial number) on the detection thresholds and vertex potentials. Generalized mixed regression and linear mixed regression were used to quantify the psychophysical detection probability and neurophysiological EEG responses, respectively. It was shown that the detection probability is significantly modulated by the stimulus amplitude, trial number, and the interaction between stimulus type and amplitude. Furthermore, EEG responses were significantly modulated by stimulus detection and trial number. Hence, we successfully demonstrated the possibility to simultaneously obtain information on psychophysical and neurophysiological properties of nociceptive processing. These results warrant further investigation of the potential of this method to observe altered nociceptive processing. [ABSTRACT FROM AUTHOR]

Transcranial static magnetic field stimulation (tSMS) is a novel and inexpensive, non-invasive brain stimulation (NIBS) technique. Here, we performed non-invasive modulation of intra-epidermal electrical stimulation-evoked potentials (IES-EPs) by applying tSMS or sham stimulation over the primary motor (M1) and somatosensory (S1) cortices in 18 healthy volunteers for 15 min. We recorded EPs after IES before, right after, and 10 min after tSMS. The IES-EP amplitude was significantly reduced immediately after tSMS over M1, whereas tSMS over S1 and sham stimulation did not affect the IES-EP amplitude. Thus, tSMS may affect cortical nociceptive processing. Although the results of intervention for experimental acute pain in healthy subjects cannot be directly translated into the clinical situation, tSMS may be a potentially useful NIBS method for managing chronic pain, in addition to standard of care treatments. [ABSTRACT FROM AUTHOR]

Healthy or pathological states of nociceptive subsystems determine different stimulus-response relations measured from quantitative sensory testing. In turn, stimulus-response measurements may be used to assess these states. In a recently developed computational model, six model parameters characterize activation of nerve endings and spinal neurons. However, both model nonlinearity and limited information in yes-no detection responses to electrocutaneous stimuli challenge to estimate model parameters. Here, we address the question whether and how one can overcome these difficulties for reliable parameter estimation. First, we fit the computational model to experimental stimulus-response pairs by maximizing the likelihood. To evaluate the balance between model fit and complexity, i.e., the number of model parameters, we evaluate the Bayesian Information Criterion. We find that the computational model is better than a conventional logistic model regarding the balance. Second, our theoretical analysis suggests to vary the pulse width among applied stimuli as a necessary condition to prevent structural non-identifiability. In addition, the numerically implemented profile likelihood approach reveals structural and practical non-identifiability. Our model-based approach with integration of psychophysical measurements can be useful for a reliable assessment of states of the nociceptive system. [ABSTRACT FROM AUTHOR]

The endogenous lipid agent N-arachidonoylethanolamine (anandamide), among other effects, has been shown to be involved in nociceptive processing both in the central and peripheral nervous systems. Anandamide is thought to be synthesised by several enzymatic pathways both in a Ca-sensitive and Ca-insensitive manner, and rat primary sensory neurons produce anandamide. Here, we show for the first time, that cultured rat primary sensory neurons express at least four of the five known Ca-insensitive enzymes implicated in the synthesis of anandamide, and that application of 1,2-dioleoyl- sn-glycero-3-phosphoethanolamine- N-arachidonoyl, the common substrate of the anandamide-synthesising pathways, results in anandamide production which is not changed by the removal of extracellular Ca. We also show that anandamide, which has been synthesised in primary sensory neurons following the application of 1,2-dioleoyl- sn-glycero-3-phosphoethanolamine- N-arachidonoyl induces a transient receptor potential vanilloid type 1 ion channel-mediated excitatory effect that is not inhibited by concomitant activation of the cannabinoid type 1 receptor. Finally, we show that sub-populations of transient receptor potential vanilloid type 1 ion channel-expressing primary sensory neurons also express some of the putative Ca-insensitive anandamide-synthesising enzymes. Together, these findings indicate that anandamide synthesised by primary sensory neuron via a Ca-insensitive manner has an excitatory rather than an inhibitory role in primary sensory neurons and that excitation is mediated predominantly through autocrine signalling. Regulation of the activity of the Ca-insensitive anandamide-synthesising enzymes in these neurons may be capable of regulating the activity of these cells, with potential relevance to controlling nociceptive processing. [ABSTRACT FROM AUTHOR]

Abstract: We have studied scalding-type burn injury-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the spinal dorsal horn, which is a recognised marker for spinal nociceptive processing. At 5min after severe scalding injury to mouse hind-paw, a substantial number of phosphorylated ERK1/2 (pERK1/2) immunopositive neurons were found in the ipsilateral dorsal horn. At 1h post-injury, the number of pERK1/2-labelled neurons remained substantially the same. However, at 3h post-injury, a further increase in the number of labelled neurons was found on the ipsilateral side, while a remarkable increase in the number of labelled neurons on the contralateral side resulted in there being no significant difference between the extent of the labelling on both sides. By 6h post-injury, the number of labelled neurons was reduced on both sides without there being significant difference between the two sides. A similar pattern of severe scalding injury-induced activation of ERK1/2 in spinal dorsal horn neurons over the same time-course was found in mice which lacked the transient receptor potential type 1 receptor (TRPV1) except that the extent to which ERK1/2 was activated in the ipsilateral dorsal horn at 5min post-injury was significantly greater in wild-type animals when compared to TRPV1 null animals. This difference in activation of ERK1/2 in spinal dorsal horn neurons was abolished within 1h after injury, demonstrating that TRPV1 is not essential for the maintenance of ongoing spinal nociceptive processing in inflammatory pain conditions in mouse resulting from at least certain types of severe burn injury. [Copyright &y& Elsevier]

ABSTRACT RX 821002 is the 2-methoxy congener of idazoxan. In binding and tissue studies it behaves as a selective antagonist of α2-adrenoceptors, with at least 5 times greater affinity for these receptors than any other binding site. It does not select between the different types of α2-receptor. Although this drug probably has no future as a therapeutic agent, it remains a good probe for physiological activity at α2-adrenoceptors in animal experiments. A particularly useful feature of this compound is its lack of binding at I1 and I2 imidazoline receptors. However, it has relatively high affinity for 5-HT1A receptors (at which it acts as an antagonist) and a tendency to behave as an inverse agonist at α2A-adrenoceptors in some cell culture systems. These potential drawbacks may be overcome by careful design of experiments, and the greater selectivity of RX 821002 renders it much superior to yohimbine or idazoxan as a tool for probing physiological actions at α2-receptors. It can be compared favorably with other selective antagonists such as atipamezole. In physiological studies, RX 821002 augments norepinephrine release in the frontal cortex and increases drinking behavior in rat. In rabbit, intrathecal administration of this drug enhances somatic and autonomic motor outflows, showing that tonic adrenergic descending inhibition of withdrawal reflexes and sympathetic pre-ganglionic neurons is strong in this species. The potentiation of reflexes may be considered a pro-nociceptive action. In the same model, RX 821002 antagonizes the inhibitory effects of the μ opioid fentanyl, indicating that exogenous opioids synergize with endogenously released norepinephrine in the spinal cord. Thus, the careful use of RX 821002 has revealed several aspects of the physiological activity of α2-adrenoceptors in rabbit spinal cord and rat brain. We recommend that RX 821002 and/or compounds with similar selectivity for α2-adrenoceptors (atipamezole, MK-912, RS-79948) should be used in preference to yohimbine or idazoxan in all future studies of this type. [ABSTRACT FROM AUTHOR]

We reviewed the records of all patients with carpal tunnel syndrome who underwent carpal tunnel release by the same neurosurgeon between 1980 and 1990. Of the total 102 patients, 71 patients (70%) had bilateral symptoms. Twenty-six patients in this group (37%) underwent bilateral surgery first on the more severely affected hand, and 1 month later on the contralateral hand. The remaining 45 patients with bilateral symptoms had surgery only on the more severely affected hand, contralateral surgery being withheld for various reasons. These 45 patients were sent follow-up questionnaires to evaluate the symptoms on the hand not treated surgically. The minimum follow up time after surgery was 14 months with an overall mean follow up of 5 years. Of the 33 respondents to the questionnaire, 15 patients stated that symptoms had disappeared in the non-operated hand, 4 said that their symptoms had improved, and 11 reported that symptoms had stayed the same. Three patients eventually underwent surgery on this previously non-operated hand. Thus, 58% of those who responded stated that; without surgery, the symptoms on their contralateral hand either improved or disappeared after surgery on the other hand. We suggest that simultaneous bilateral carpal tunnel surgery may be unnecessary for some patients with bilateral symptoms. [ABSTRACT FROM AUTHOR]