Differences in intracortical responses following non-noxious and noxious stimulation in anaesthetized rats.

Cortical responses have been proposed as a source for the extraction of unique and non-subjective sensory information. The present study aimed to investigate if it is possible to distinguish between non-noxious and noxious cortical responses with two different types of anesthesia. Sixteen rats were randomly allocated to receive either Hypnorm/Dormicum (HD) or isoflurane (ISO) anesthesia. Each animal had a custom-made microelectrode array implanted in the primary somatosensory cortex to record the local field potentials and a cuff electrode implanted around the sciatic nerve to deliver electrical stimulations. Three stimulation intensities were applied: 1x movement threshold (MT) (i.e., non-noxious activation), 5x MT (low intensity noxious activation), and 10x MT (high intensity noxious activation). The evoked potentials were assessed by extracting three features: 1) the negative peak (NP), 2) the positive peak (PP), and 3) the peak-to-peak (PtP) amplitudes. Our results showed that it was possible to distinguish between three levels of stimulation intensities based on the NP, PP, and PtP features for the HD group, whereas it was only possible to make the same differentiation with the use of PP and PtP when applying ISO. This work is believed to contribute to a basic understanding of how the cortical responses change in the hyperacute phase of pain and which cortical features may be suitable as objective measures of nociception.

Directional discrimination is better for noxious laser stimuli than for innocuous laser stimuli.

BACKGROUND: The directional discrimination is lower for painful laser heat compared to non-painful mechanical stimulation. The aim of the current study was to investigate how the directional discrimination of radiant heat stimulation depends on stimulation intensity and displacement velocity. METHODS: Fifteen healthy subjects were stimulated in the right volar forearm with a CO2 laser at intensities that were expected to be either painful (46°C) or non-painful (39°C). The laser beam was continuously displaced distal-proximally along the arm during the stimulation. After the stimulation, subjects indicated the perceived direction and intensity (NRS: 0: perception 3: pain 10: maximum pain). Stimulations were delivered with five lengths (20, 40, 60, 80 and 100 mm) and three velocities (10, 30 and 100 mm/s). To estimate the directional discrimination threshold (DDT) the data were fitted to a sigmoidal curve. RESULTS: For the lower intensity (39°C) the DDT was 81.8 mm for the slowest velocity, and above 100 mm for the two faster velocities. For the higher intensity (46°C) the DDT was 58.8 and 69.6 mm for the slowest velocity and middle velocity, respectively, and above 100 mm for the fastest velocity. The perceived intensity increased with stimulation length, stimulation intensity and decreasing velocity (LMM, p < .001). CONCLUSIONS: This study shows how the DDT for thermal stimuli is shorter for higher intensity and lower displacement velocities. Additionally, it was shown that for the velocity where directional discrimination is optimal for mechanical stimuli it is not possible to discriminate a thermal stimulus. SIGNIFICANCE: This study showed that the directional discrimination of painful laser stimuli is better than that for non-painful laser stimuli. These findings supplements our current knowledge regarding the tempo-spatial discrimination in the nociceptive system, where evidence from previous discrimination studies differs somewhat regarding difference between painful and non-painful discrimination. This, therefore, indicates that there is lacking knowledge regarding the discrimination within the nociceptive system.

Electrical stimulation for evoking offset analgesia: A human volunteer methodological study.

BACKGROUND: Offset analgesia (OA) is a disproportionally large decrease in the pain perception in response to a small decrease in the stimulation intensity. Traditionally, heat stimulation has been used to evoke OA. The aim of this study was to investigate whether OA could be evoked by electrical stimulation. METHODS: Healthy volunteers (N = 24) underwent two OA-experimental sessions consisting of heat stimuli intensities of 48-49-48 °C (traditional OA-paradigm) and electrical stimuli at 150%-180%-150% of the electrical pain perception (EPP) threshold. The three stimuli were delivered for 5 s (STIM1), 5 s (STIM2) and 20 s (STIM3), respectively. The sessions were randomized to the dominant or nondominant volar forearm. Two control sessions were performed with 30 s constantly heat (48 °C) and electrical stimuli (150% of the EPP) (CONTROL-STIM). In all sessions, the pain intensities were constantly rated on a Visual Analog Scale (VAS, 0-10). RESULTS: Significantly reduced STIM3 VAS ratings as compared to the CONTROL-STIM were reported for heat (1.81 ± 0.54; p < 0.001) and electrical (2.12 ± 0.42; p < 0.001) stimuli. The degrees of OA produced by heat and electrical stimuli were similar. A significantly positive correlation was found between thermal and electrical OA-effects (r = 0.48, p < 0.02). CONCLUSIONS: These findings demonstrate that electrical stimulation can elicit significant OA in humans indicating that the peripheral receptors can be bypassed and still evoke OA. Application of the electrical OA model may be of interest for further basic and clinical investigations as a potential new biomarker for central pain inhibition and provide the option to back-translate the technology to animals to understand the underlying neurobiology. SIGNIFICANCE: Electrical stimulation can elicit offset analgesia in humans, indicating that this perceptual modification can be obtained even bypassing peripheral receptors.

Offset analgesia: The role of peripheral and central mechanisms.

BACKGROUND: Offset Analgesia (OA) can be evoked by a three-heat-stimulus train (T1-T2-T3), with T1 (5 s) and T3 (20 s) having the same temperature (e.g. 48 °C) and T2 (5 s) being slightly higher (1-3 °C). OA is defined as a disproportional pain reduction caused by the slight temperature decrease from T2 to T3. As the pain modulatory mechanisms behind OA are still poorly understood, the current study aimed to investigate the role of peripheral and central mechanisms by applying heat stimuli to the same location and to different unilateral and bilateral locations. METHOD: Young healthy volunteers participated in the study. A 'standard-OA' paradigm (48-49-48 °C) was applied to the non-dominant volar forearm (T1-T2-T3 applied on the same location). 'Unilateral-OA' trials were applied on three different locations of the non-dominant volar forearm (the same dermatome). 'Bilateral-OA' trials were applied by shifting T1-T2-T3 between dominant and non-dominant volar forearms. A constant stimulus of 48 °C was applied as control for the evoked pain. The pain intensities were continuously recorded using an electronic visual analogue scale. RESULTS: The largest pain intensity reduction was reported for the 'standard-OA' paradigm (p < 0.001) compared with the control stimulus. Both 'Unilateral-OA' and 'Bilateral-OA' trials caused a significant pain reduction (p < 0.05) compared with the control; however, the pain reduction was less than that evoked by 'standard-OA' (p < 0.05). CONCLUSION: This study showed that OA could be elicited when the stimuli were applied both to the same and to different locations (ipsi- and contralateral) indicating that peripheral as well as central mechanisms are involved in mediating OA. SIGNIFICANCE: This study investigated offset analgesia by applying thermal painful stimuli to the ipsi- and bilateral forearms in healthy subjects and found that both peripheral and central mechanisms seem to mediate offset analgesia.

Exploration of conditioned pain modulation effect on long-term potentiation-like pain amplification in humans.

BACKGROUND: This study aimed to explore conditioned pain modulation (CPM) effect on long-term potentiation (LTP)-like pain amplification induced by cutaneous 10-Hz conditioning electrical stimulation (CES). METHODS: Conditioned pain modulation was induced by cold pressor conditioning stimulus (CPCS) (4 °C) which was applied immediately before CES in the active session. In the control session, water with a temperature of 32 °C was used. Twenty subjects participated in two sessions in a randomized crossover design with at least 1-week interval. Perceptual intensity ratings to single electrical stimulation (SES) at the conditioned skin site and to pinprick and light-stroking stimuli in the immediate vicinity of the CES electrodes were measured . Superficial blood flow (SBF), skin temperature (ST) and heat pain threshold (HPT) were measured covering both homotopic and heterotopic skin. The pain intensities during CES process were measured and short-form McGill Pain Questionnaire (SF-MPQ) was used for assessing CES pain experience. RESULTS: Cold pressor conditioning stimulus reduced pain perception increments to weak pinprick and light-stroking stimuli after 10-Hz CES compared with the control session. Moreover, CPCS resulted in lower pain intensity ratings during CES process but without affecting the SF-MPQ scores between two sessions. The SBF and ST increased after CES and then gradually declined but without differences between CPCS and control sessions. CPM did not affect HPT and pain intensity increments to SES. CONCLUSIONS: The CPCS inhibited heterotopic perception amplification to weak mechanical stimuli after CES. The results indicate that endogenous descending inhibitory systems might play a role against development of non-nociceptive perception amplificatory states (e.g. allodynia). SIGNIFICANCE: Conditioned pain modulation (CPM) may play a role in inhibiting the pain amplificatory process at the central nervous system and prompting central desensitization. CPM has a special inhibition effect for the development of perception amplification to non-painful mechanical stimuli.

Cortical and spinal assessment - a comparative study using encephalography and the nociceptive withdrawal reflex.

BACKGROUND: Standardized objective methods to assess the analgesic effects of opioids, enable identification of underlying mechanisms of drug actions in the central nervous system. Opioids may exert their effect on both cortical and spinal levels. In this study actions of morphine at both levels were investigated, followed by analysis of a possible correlation between the cortical processing and spinal transmission. METHODS: The study was conducted after a double-blinded, two-way crossover design in thirty-nine healthy participants. Each participant received 30mg morphine or placebo as oral solution in randomized order. The electroencephalogram (EEG) was recorded during rest and during immersion of the hand into ice-water. Electrical stimulation of the sole of the foot was used to elicit the nociceptive withdrawal reflex and the reflex amplitude was recorded. RESULTS: Data from thirty subjects was included in the data analysis. There was no change in the activity in resting EEG (P>0.05) after morphine administration as compared to placebo. During cold pressor stimulation, morphine significantly lowered the relative activity in the delta (1-4Hz) band (P=0.03) and increased the activity in the alpha (8-12Hz) band (P=0.001) as compared to placebo. The reflex amplitudes significantly decreased after morphine administration (P=0.047) as compared to placebo. There was no correlation between individual EEG changes during cold pressor stimulation and the decrease in the reflex amplitude after morphine administration (P>0.05). CONCLUSIONS: Cold pressor EEG and the nociceptive reflex were more sensitive to morphine analgesia than resting EEG and can be used as standardized objective methods to assess opioid effects. However, no correlation between the analgesic effect of morphine on the spinal and cortical assessments could be demonstrated.

Venlafaxine and oxycodone effects on human spinal and supraspinal pain processing: a randomized cross-over trial.

Severe pain is often treated with opioids. Antidepressants that inhibit serotonin and norepinephrine reuptake (SNRI) have also shown a pain relieving effect, but for both SNRI and opioids, the specific mode of action in humans remains vague. This study investigated how oxycodone and venlafaxine affect spinal and supraspinal pain processing. Twenty volunteers were included in this randomized cross-over study comparing 5-day treatment with venlafaxine, oxycodone and placebo. As a proxy of the spinal pain transmission, the nociceptive withdrawal reflex (NWR) to electrical stimulation on the sole of the foot was recorded at the tibialis anterior muscle before and after 5 days of treatment. For the supraspinal activity, 61-channel electroencephalogram evoked potentials (EPs) to the electrical stimulations were simultaneously recorded. Areas under curve (AUCs) of the EMG signals were analyzed. Latencies and AUCs were computed for the major EP peaks and brain source analysis was done. The NWR was decreased in venlafaxine arm (P = 0.02), but the EP parameters did not change. Oxycodone increased the AUC of the EP response (P = 0.04). Oxycodone also shifted the cingulate activity anteriorly in the mid-cingulate-operculum network (P < 0.01), and the cingulate activity was increased while the operculum activity was decreased (P = 0.02). Venlafaxine exerts its effects on the modulation of spinal nociceptive transmission, which may reflect changes in balance between descending inhibition and descending facilitation. Oxycodone, on the other hand, exerts its effects at the cortical level. This study sheds light on how opioids and SNRI drugs modify the human central nervous system and where their effects dominate.

Comparing test-retest reliability and magnitude of conditioned pain modulation using different combinations of test and conditioning stimuli.

This study aimed to compare the reliability and magnitude of conditioned pain modulation (CPM) by applying different test stimuli (TS) and conditioning stimuli (CS). Twenty-six healthy male participants were recruited in the study of two identical sessions. In each session, four TS (electrical, heat, handheld, and cuff pressure algometry) were applied before and during CS (cold pressor test (CPT) or cuff algometry). The same procedure was repeated with 45-min intervals, but with the other CS. Five thresholds were measured including four pain detection thresholds from four TS and pain tolerance threshold from cuff TS (cuff PTT). Intraclass correlation coefficient (ICC (3,1)) and coefficient of variation (CV) were calculated as measures of reliability. The reliability of TS before and during CS was good for all combinations (ICC: 0.60-0.96, CV: 2.2-22.9%), but the reliability of the CPM effect varied (ICC: 0.04-0.53, CV: 63.6-503.9%). The most reliable combinations were considered to be the handheld pressure pain threshold with CPT (ICC: 0.49, CV: 63.6%) and the cuff pressure pain threshold with CPT (ICC: 0.44, CV: 107.6%). Significant CPM effects were found for all combinations, except the combinations of electrical and heat pain thresholds with cuff CS, which indicates the novel classification of the CPM mechanism. The combinations of handheld pressure and heat pain threshold with CPT would provide the minimum sample size to detect the significant CPM changes in further studies. It is beneficial to provide and compare both ICC and CV to design further clinical trials.

Differences in perception and brain activation following stimulation by large versus small area cutaneous surface electrodes.

INTRODUCTION: Application of electrical stimulation through conventional surface electrodes activates both non-nociceptive and nociceptive fibres. To encompass this problem, electrical stimulation through small area pin electrode was introduced where subjective description of stimulation quality indicated preferential activation of nociceptors. The present study aimed to show that brain areas involved in nociceptive processing are activated by stimulation through cutaneous pin electrode (CPE) to a larger extent than conventional surface electrodes. METHODS: Evoked potentials (EPs) were induced by electrical stimulation through conventional surface and CPE electrodes. The EPs were recorded from 62 scalp electrodes in 12 healthy volunteers where stimulation intensity was 10 times the sensory threshold. Dipolar models of brain sources were built by using the brain electrical source analysis. RESULTS: The solution for the conventional large area surface electrode was a four-dipole model including contralateral primary somatosensory cortex, bilateral secondary somatosensory cortex (SII) and mid-cingulate sources. The solution for CPE was a five-dipole model and very similar to that previously described to explain the topography of laser EPs. The solution included bilateral SII, bilateral insula and mid-cingulate sources. Since laser stimuli mainly activate nociceptive fibres, the strong similarity suggests that mainly nociceptive inputs are involved in generation of CPE-evoked responses. CONCLUSION: The current study gives evidence that CPE activates the nociceptive brain areas to a greater extent than conventional surface electrode. Therefore, CPE should preferentially be utilized in future studies where electrical stimuli are used to study nociception.

Dynamic tuning of human withdrawal reflex receptive fields during cognitive attention and distraction tasks.

OBJECTIVES: The aim of the present study was to investigate supraspinal modulation of human lower limb reflex receptive fields (RRFs) on the plantar side of the foot during cognitive tasks either distracting the subjects or actively directing their attention to the electrical stimuli directed to the sole of the foot. METHODS: Twelve healthy volunteers participated. Nociceptive withdrawal reflexes (NWRs) were recorded in the ankle flexor tibialis anterior. The RRF was acquired by randomized activation of ten stimulation sites on the sole of the foot. The RRF was assessed during baseline, distraction, and attention in randomized order. Distraction was induced by the Stroop test, while attention was induced by requiring the subjects to localize the site of the stimulation and thereby forcing them to focus on the sole of the foot. RESULTS: The area of the RRF was significantly enlarged during the distraction task compared to baseline (P<0.05), whereas the RRF area was significantly reduced during the attention task compared to baseline (P<0.05). CONCLUSION: The size of the RRF area was modulated by the cognitive state demonstrating a link between the cognitive activity and the descending control on spinal withdrawal reflex pathways.

Convergence of cutaneous, musculoskeletal, dural and visceral afferents onto nociceptive neurons in the first cervical dorsal horn.

The convergence of cutaneous, musculoskeletal, dural and visceral afferents onto nociceptive neurons in the first cervical dorsal horn was investigated in urethane/chloralose-anesthetized rats. Electrical stimulation was applied to facial, neck, shoulder and forepaw skin, cornea (COR), dura, second cervical (C2) nerve, hypoglossal nerve, temporomandibular joint, masseter (MAS) muscle and superior laryngeal nerve. In addition, acetic acid was injected intraperitoneally and microinjection of glutamate was applied to the tongue, MAS muscle, splenius cervicis muscle, dura and intrapericardial area. A total of 52 nociceptive neurons classified as wide dynamic range (n = 28) or nociceptive-specific (n = 24) was studied. All nociceptive neurons received afferent input from the skin and at least one COR, musculoskeletal, dural or visceral afferent source in the trigeminal (V) or cervical area but input from afferent sources caudal to the C2 innervation territory was sparse. The proportion of neurons responding to COR, dural, C2 nerve, hypoglossal nerve, temporomandibular joint, MAS muscle and superior laryngeal nerve stimulations was 87, 54, 85, 52, 73, 64 and 31%, respectively. Electrical stimulation of all tested sites showed a double logarithmic stimulus-response relation, and cluster analysis of the excitability to COR, musculoskeletal, dural and visceral stimulations revealed two groups of neurons, one mainly containing wide dynamic range neurons and one mainly containing nociceptive-specific neurons. These findings indicate that afferent convergence in first cervical dorsal horn nociceptive neurons may be limited to the craniofacial area and that they may play an important role in the integration of craniofacial and upper cervical nociceptive inputs.

Differential antinociceptive effects induced by a selective cyclooxygenase-2 inhibitor (SC-236) on dorsal horn neurons and spinal withdrawal reflexes in anesthetized spinal rats.

The aim of present study was to examine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor SC-236 (4 mg/kg) on the simultaneous responsiveness of spinal wide-dynamic range (WDR) neurons and single motor units (SMUs) from gastrocnemius soleus muscles to mechanical stimuli (pressure and pinch) and repeated suprathreshold (1.5xT, the intensity threshold) electrical stimuli with different frequencies (3 Hz, 20 Hz) under normal conditions and bee venom (BV, 0.2 mg/50 microl)-induced inflammation and central sensitization. During normal conditions, the responses of SMUs, but not WDR neurons, to mechanical and repeated electrical stimuli (3 Hz, wind-up) were depressed by systemic administration of SC-236 as well as its vehicle (100% dimethyl sulfoxide (DMSO)). The after-discharges of both the WDR neurons and the simultaneously recorded SMUs after electrical stimuli with 20 Hz were markedly depressed only by SC-236, indicating that the mechanisms underlying the generation of the C-fiber mediated late responses and the after-discharges may be different. The enhanced responsiveness of both WDR neurons and SMUs to mechanical pressure stimuli (allodynia) and pinch stimuli (hyperalgesia) in the BV experiments was apparently depressed by SC-236, but not its vehicle. For electrical stimulation, the enhanced late responses and after-discharges, but not early responses, of both the WDR neurons and the simultaneously recorded SMUs were markedly depressed only by SC-236. This indicates that different central pharmacological mechanisms underlie the generation of these enhanced early, late responses, and after-discharges during BV-induced inflammation. The data suggest that the COX-2 inhibitor SC-236 apparently depress the activities of both spinal cord dorsal horn neuron and spinal withdrawal reflex during BV-induced sensitization, indicating that COX-2 plays an important role in the maintenance of central sensitization.