Mikhail I. Nemenov

All Publications

• Paradoxical Increases in Anterior Cingulate Cortex Activity During Volatile Anesthetic-Induced Analgesia in Mice Weinrich, J., Jewell, M., Liu, C., Andolina, C., Nemenov, M., Maze, M., Basbaum, A. LIPPINCOTT WILLIAMS & WILKINS. 2023: 518

  View details for Web of Science ID 001058985600183

• Paradoxical increases in anterior cingulate cortex activity during nitrous oxide-induced analgesia reveal a signature of pain affect. bioRxiv : the preprint server for biology Weinrich, J. A., Liu, C. D., Jewell, M. E., Andolina, C. R., Bernstein, M. X., Benitez, J., Rodriguez-Rosado, S., Braz, J. M., Maze, M., Nemenov, M. I., Basbaum, A. I. 2023

  Abstract

  The general consensus is that increases in neuronal activity in the anterior cingulate cortex (ACC) contribute to pain's negative affect. Here, using in vivo imaging of neuronal calcium dynamics in mice, we report that nitrous oxide, a general anesthetic that reduces pain affect, paradoxically, increases ACC spontaneous activity. As expected, a noxious stimulus also increased ACC activity. However, as nitrous oxide increases baseline activity, the relative change in activity from pre-stimulus baseline was significantly less than the change in the absence of the general anesthetic. We suggest that this relative change in activity represents a neural signature of the affective pain experience. Furthermore, this signature of pain persists under general anesthesia induced by isoflurane, at concentrations in which the mouse is unresponsive. We suggest that this signature underlies the phenomenon of connected consciousness, in which use of the isolated forelimb technique revealed that pain percepts can persist in anesthetized patients.

  View details for DOI 10.1101/2023.04.03.534475

  View details for PubMedID 37066151

  View details for PubMedCentralID PMC10104003

• Evaluation of a polymer coated nanoparticle cream formulation of resiniferatoxin for the treatment of painful diabetic peripheral neuropathy. Pain Baskaran, P., Mohandass, A., Gustafson, N., Bennis, J., Louis, S., Alexander, B., Nemenov, M. I., Thyagarajan, B., Premkumar, L. S. 2022

  Abstract

  Painful Diabetic Peripheral Neuropathy (PDPN) is one of the major complications of diabetes. Currently, centrally acting drugs and topical analgesics are used for treating PDPN. These drugs have adverse effects, some are ineffective and treatment with opioids is associated with use dependence and addiction. Recent research indicates that Transient Receptor Potential Vanilloid 1 (TRPV1) expressed in the peripheral sensory nerve terminals is an emerging target to treat pain associated with PDPN. Blocking TRPV1 ion channel using specific antagonists, although effective as an analgesic, but induced hyperthermia in clinical trials. However, TRPV1 agonists are useful to treat pain by virtue of their ability to cause Ca2+ influx and subsequently leading to nerve terminal desensitization. Here, we report the effectiveness of an ultra-potent TRPV1 agonist, resiniferatoxin (RTX) nanoparticle in a topical formulation (RTX-cream; RESINIZINTM) that alleviates pain associated with DPN in animal models of diabetes. RTX causes nerve terminal depolarization block in the short-term, which prevents pain during application and leading to nerve terminal desensitization/depletion in the long-term resulting in long lasting pain relief. Application of RTX cream to the hind limbs suppresses thermal hyperalgesia in streptozotocin (STZ)-induced diabetic rats and mini-pigs without any adverse effects as compared to capsaicin at therapeutic doses, which induces intense pain during application. RTX cream also decreases the expression of TRPV1 in the peripheral nerve endings and suppresses TRPV1-mediated CGRP release in the skin samples of diabetic rats and mini-pigs. Our preclinical data confirm that RTX topical formulation is an effective treatment option for PDPN.

  View details for DOI 10.1097/j.pain.0000000000002765

  View details for PubMedID 36001079

• Assessing the Analgesic Properties of Volatile Anesthetics Using High-Power Infrared Lasers in Mice Weinrich, J., Jewell, M. E., Andolina, C. R., Liu, C. D., Nemenov, M. I., Maze, M., Basbaum, A. LIPPINCOTT WILLIAMS & WILKINS. 2022: 565

  View details for Web of Science ID 000840283000225

• Characterization of patients with and without painful peripheral neuropathy after receiving neurotoxic chemotherapy: traditional quantitative sensory testing vs C-fiber and Adelta-fiber selective diode laser stimulation. The journal of pain Nemenov, M. I., Alaverdyan, H., Burk, C., Roles, K., Frey, K., Yan, Y., Kazinets, G., Haroutounian, S. 1800

  Abstract

  Painful chemotherapy induced peripheral neuropathy (CIPN) is a common complication of chemotherapy with drugs such as taxanes and platinum compounds. Currently, no methods are available for early detection of sensory changes that are associated with painful CIPN, nor are there biomarkers that are specific to painful CIPN. This study aimed to compare Diode Laser fiber type-selective stimulator (DLss), a method to selectively stimulate cutaneous C and Adelta fibers, to traditional quantitative sensory testing (QST) in determining psychophysical differences between patients with painful CIPN and a control group. Sensory testing was performed on the dorsal mid-foot of 20 patients with painful neuropathy after taxane- or platinum-based chemotherapy, and 20 patients who received similar neurotoxic chemotherapy, without painful CIPN. In a multivariable analysis, C-fiber to Adelta fiber detection threshold ratio, measured by DLss, was significantly different between the groups (p<0.05). While QST parameters such as warmth detection threshold were different between the groups in univariate analyses, these findings were likely attributable to group differences in patient age and cumulative chemotherapy dose. PERSPECTIVE: In this study, fiber-specific DLss test showed potential in identifying sensory changes that are specific for painful neuropathy, encouraging future testing of this approach as a biomarker for early detection of painful CIPN. TRIAL REGISTRATION: The study was approved by the Washington University Institutional Review Board (#201807162) and registered at ClinicalTrials.gov (NCT03687970).

  View details for DOI 10.1016/j.jpain.2021.11.011

  View details for PubMedID 34896646

• Role of Mechanoinsensitive Nociceptors in Painful Diabetic Peripheral Neuropathy. Current diabetes reviews Nemenov, M. I., Singleton, R. J., Premkumar, L. S. 2021

  Abstract

  The cutaneous mechanisms that trigger spontaneous neuropathic pain in diabetic peripheral neuropathy (PDPN) are far from clear. Two types of nociceptors are found within the epidermal and dermal skin layers. Small-diameter lightly myelinated Adelta and unmyelinated C cutaneous mechano and heat sensitive (AMH and CMH) and C mechanoinsensitive (CMi) nociceptors transmit pain from the periphery to central nervous system. AMH and CMH fibers are mainly located in the epidermis and CMi fibers are distributed in the dermis. In DPN, dying back intra-epidermal AMH and CMH fibers leads to reduced pain sensitivity and the patients exhibit significantly increased pain thresholds to acute pain, when tested using traditional methods. The role of CMi fibers in painful neuropathies has not been fully explored. Microneurography has been the only tool to access CMi fibers and differentiate AMH, CMH and CMi fiber types. Due to the complexity, its use is impractical in clinical settings. In contrast, a newly developed diode laser fiber selective stimulation (DLss) technique allows to safely and selectively stimulate Adelta and C fibers in the superficial and deep skin layers. DLss data demonstrate that patients with painful DPN have increased Adelta fiber pain thresholds, while C-fiber thresholds are intact because in these patients CMi fibers are abnormally spontaneously active. It is also possible to determine the involvement of CMi fibers by measuring the area of DLss-induced neurogenic axon reflex flare. The differences in AMH, CMH and CMi fibers allow to identify patients with painful and painless neuropathy. In this review, we will discuss the role of CMi fibers in PDPN.

  View details for DOI 10.2174/1573399818666211208101555

  View details for PubMedID 34879806

• Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion. Pain Mitchell, K., Lebovitz, E. E., Keller, J. M., Mannes, A. J., Nemenov, M. I., Iadarola, M. J. 2014; 155 (4): 733-745

  Abstract

  TRPV1 is expressed in a subpopulation of myelinated Aδ and unmyelinated C-fibers. TRPV1+ fibers are essential for the transmission of nociceptive thermal stimuli and for the establishment and maintenance of inflammatory hyperalgesia. We have previously shown that high-power, short-duration pulses from an infrared diode laser are capable of predominantly activating cutaneous TRPV1+ Aδ-fibers. Here we show that stimulating either subtype of TRPV1+ fiber in the paw during carrageenan-induced inflammation or following hind-paw incision elicits pronounced hyperalgesic responses, including prolonged paw guarding. The ultrapotent TRPV1 agonist resiniferatoxin (RTX) dose-dependently deactivates TRPV1+ fibers and blocks thermal nociceptive responses in baseline or inflamed conditions. Injecting sufficient doses of RTX peripherally renders animals unresponsive to laser stimulation even at the point of acute thermal skin damage. In contrast, Trpv1-/- mice, which are generally unresponsive to noxious thermal stimuli at lower power settings, exhibit withdrawal responses and inflammation-induced sensitization using high-power, short duration Aδ stimuli. In rats, systemic morphine suppresses paw withdrawal, inflammatory guarding, and hyperalgesia in a dose-dependent fashion using the same Aδ stimuli. The qualitative intensity of Aδ responses, the leftward shift of the stimulus-response curve, the increased guarding behaviors during carrageenan inflammation or after incision, and the reduction of Aδ responses with morphine suggest multiple roles for TRPV1+ Aδ fibers in nociceptive processes and their modulation of pathological pain conditions.

  View details for DOI 10.1016/j.pain.2014.01.007

  View details for PubMedID 24434730

• Sensory Small Fiber Function Differentially Assessed with Diode Laser (DL) Quantitative Sensory Testing (QST) in Painful Neuropathy (PN) PAIN MEDICINE Moeller-Bertram, T., Schilling, J. M., Backonja, M. M., Nemenov, M. I. 2013; 14 (3): 417-421

  Abstract

  Sensory function of small peripheral nerve fiber was assessed by means of quantitative sensory testing (QST) during which sensory stimulation was provided using diode laser (DL) in patients suffering from painful neuropathy (PN) and compared with symptom-free healthy controls (HC). Based on previous research work using DL stimulation, parameters that demonstrated safe and specific activation of A-delta, which were distinct from stimulation parameters for the activation of C-fibers, were utilized in this study. Results of this study demonstrated that this differential activation pointed to the impaired function of A-delta fibers while C-fiber function was unaffected. Stimulation of HC reproduced previously published results, and stimulation during this study was safe also without any dermal effect in patients with PN and in HC. Parameters used in this study were demonstrated in previous preclinical rodent study identical differential effect on activation of A-delta and C-fibers, and as such, DL is an ideal tool for translational pain research where specific activation of A-delta or C-fibers, or both, is required.

  View details for DOI 10.1111/pme.12049

  View details for Web of Science ID 000316210600020

  View details for PubMedID 23433028

• The modality-specific contribution of peptidergic and non-peptidergic nociceptors is manifest at the level of dorsal horn nociresponsive neurons JOURNAL OF PHYSIOLOGY-LONDON Zhang, J., Cavanaugh, D. J., Nemenov, M. I., Basbaum, A. I. 2013; 591 (4): 1097-1110

  Abstract

  We previously demonstrated that genetic and/or pharmacological ablation of the TRPV1+/peptidergic or the MrgprD+/non-peptidergic subset of nociceptors produced selective, modality-specific deficits in the behavioural responses to heat and mechanical stimuli, respectively. To assess whether this modality-specific contribution is also manifest at the level of spinal cord neuron responsiveness, here we made extracellular recordings from lumbar dorsal horn neurons of the mouse in response to graded thermal and mechanical stimulation. We found that, following intrathecal injection of capsaicin to eliminate the central terminals of TRPV1+ nociceptors, neurons in the region of laminae I and V of the spinal cord lost responsiveness to noxious heat (whether generated by a contact heat probe or diode laser), with no change in their response to noxious mechanical stimulation. In contrast, ablation of MrgprD+ afferents did not alter the response to noxious heat, but reduced the firing of superficial dorsal horn nociceptive-specific neurons in response to graded mechanical stimulation and decreased the relative number of wide dynamic range neurons that were exclusively mechanosensitive. Neither ablation procedure reduced the number of dorsal horn neurons that responded to noxious cold. These findings support the conclusion that TRPV1+ nociceptors are necessary and probably sufficient for noxious heat activation of dorsal horn neurons and that, despite their polymodal properties, TRPV1+ and MrgprD+ nociceptors provide modality-specific contributions to the response properties of spinal cord neurons.

  View details for DOI 10.1113/jphysiol.2012.242115

  View details for Web of Science ID 000315150000027

  View details for PubMedID 23266932

  View details for PubMedCentralID PMC3591717

• Selective nociceptor activation in volunteers by infrared diode laser MOLECULAR PAIN Tzabazis, A. Z., Klukinov, M., Crottaz-Herbette, S., Nemenov, M. I., Angst, M. S., Yeomans, D. C. 2011; 7

  Abstract

  Two main classes of peripheral sensory neurons contribute to thermal pain sensitivity: the unmyelinated C fibers and thinly myelinated Aδ fibers. These two fiber types may differentially underlie different clinical pain states and distinctions in the efficacy of analgesic treatments. Methods of differentially testing C and Aδ thermal pain are widely used in animal experimentation, but these methods are not optimal for human volunteer and patient use. Thus, this project aimed to provide psychophysical and electrophysiological evidence that whether different protocols of infrared diode laser stimulation, which allows for direct activation of nociceptive terminals deep in the skin, could differentially activate Aδ or C fiber thermonociceptors in volunteers.Short (60 ms), high intensity laser pulses (SP) evoked monomodal "pricking" pain which was not enhanced by topical capsaicin, whereas longer, lower power pulses (LP) evoked monomodal "burning" pain which was enhanced by topical capsaicin. SP also produced cortical evoked EEG potentials consistent with Aδ mediation, the amplitude of which was directly correlated with pain intensity but was not affected by topical capsaicin. LP also produced a distinct evoked potential pattern the amplitude of which was also correlated with pain intensity, which was enhanced by topical capsaicin, and the latency of which could be used to estimate the conduction velocity of the mediating nociceptive fibers.Psychophysical and electrophysiological data were consistent with the ability of short high intensity infrared laser pulses to selectively produce Aδ mediated pain and of longer pulses to selectively produce C fiber mediated thermal pain. Thus, the use of these or similar protocols may be useful in developing and testing novel therapeutics based on the differential molecular mechanisms underlying activation of the two fiber types (e.g., TRPV1, TRPV2, etc). In addition, these protocol may be useful in determining the fiber mediation of different clinical pain types which may, in turn be useful in treatment choice.

  View details for DOI 10.1186/1744-8069-7-18

  View details for Web of Science ID 000289115700001

  View details for PubMedID 21426575

  View details for PubMedCentralID PMC3070669

• Ablation of rat TRPV1-expressing Adelta/C-fibers with resiniferatoxin: analysis of withdrawal behaviors, recovery of function and molecular correlates MOLECULAR PAIN Mitchell, K., Bates, B. D., Keller, J. M., Lopez, M., Scholl, L., Navarro, J., Madian, N., Haspel, G., Nemenov, M. I., Iadarola, M. J. 2010; 6

  Abstract

  Ablation of TRPV1-expressing nociceptive fibers with the potent capsaicin analog resiniferatoxin (RTX) results in long lasting pain relief. RTX is particularly adaptable to focal application, and the induced chemical axonopathy leads to analgesia with a duration that is influenced by dose, route of administration, and the rate of fiber regeneration. TRPV1 is expressed in a subpopulation of unmyelinated C- and lightly myelinated Adelta fibers that detect changes in skin temperature at low and high rates of noxious heating, respectively. Here we investigate fiber-type specific behaviors, their time course of recovery and molecular correlates of axon damage and nociception using infrared laser stimuli following an RTX-induced peripheral axonopathy.RTX was injected into rat hind paws (mid-plantar) to produce thermal hypoalgesia. An infrared diode laser was used to stimulate Adelta fibers in the paw with a small-diameter (1.6 mm), high-energy, 100 msec pulse, or C-fibers with a wide-diameter (5 mm), long-duration, low-energy pulse. We monitored behavioral responses to indicate loss and regeneration of fibers. At the site of injection, responses to C-fiber stimuli were significantly attenuated for two weeks after 5 or 50 ng RTX. Responses to Adelta stimuli were significantly attenuated for two weeks at the highest intensity stimulus, and for 5 weeks to a less intense Adelta stimulus. Stimulation on the toe, a site distal to the injection, showed significant attenuation of Adelta responses for 7- 8 weeks after 5 ng, or 9-10 weeks after 50 ng RTX. In contrast, responses to C-fiber stimuli exhibited basically normal responses at 5 weeks after RTX. During the period of fiber loss and recovery, molecular markers for nerve regeneration (ATF3 and galanin) are upregulated in the dorsal root ganglia (DRG) when behavior is maximally attenuated, but markers of nociceptive activity (c-Fos in spinal cord and MCP-1 in DRG), although induced immediately after RTX treatment, returned to normal.Behavioral recovery following peripheral RTX treatment is linked to regeneration of TRPV1-expressing Adelta and C-fibers and sustained expression of molecular markers. Infrared laser stimulation is a potentially valuable tool for evaluating the behavioral role of Adelta fibers in pain and pain control.

  View details for DOI 10.1186/1744-8069-6-94

  View details for Web of Science ID 000286116100001

  View details for PubMedID 21167052

  View details for PubMedCentralID PMC3019206

• Thermal nociceptive properties of trigeminal afferent neurons in rats MOLECULAR PAIN Cuellar, J. M., Manering, N. A., Klukinov, M., Nemenov, M. I., Yeomans, D. C. 2010; 6

  Abstract

  Although nociceptive afferents innervating the body have been heavily studied form many years, much less attention has been paid to trigeminal afferent biology. In particular, very little is known concerning trigeminal nociceptor responses to heat, and almost nothing in the rat. This study uses a highly controlled and reproducible diode laser stimulator to investigate the activation of trigeminal afferents to noxious skin heating.The results of this experiment demonstrate that trigeminal thermonociceptors are distinct from themonociceptors innervating the limbs. Trigeminal nociceptors have considerably slower action potential conduction velocities and lower temperature thresholds than somatic afferent neurons. On the other hand, nociceptors innervating both tissue areas separate into those that respond to short pulse, high rate skin heating and those that respond to long pulse, low rate skin heating.This paper provides the first description in the literature of the in vivo properties of thermonociceptors in rats. These finding of two separate populations aligns with the separation between C and A-delta thermonociceptors innervating the paw, but have significant differences in terms of temperature threshold and average conduction velocities. An understanding of the temperature response properties of afferent neurons innervating the paw skin have been critical in many mechanistic discoveries, some leading to new pain therapies. A clear understanding of trigeminal nociceptors may be similarly useful in the investigation of trigeminal pain mechanisms and potential therapies.

  View details for DOI 10.1186/1744-8069-6-39

  View details for PubMedID 20609212

• Differential brain activation associated with laser-evoked burning and pricking pain: An event-related fMRI study PAIN Veldhuijzen, D. S., Nemenov, M. I., Keaser, M., Zhuo, J., Gullapalli, R. P., Greenspan, J. D. 2009; 141 (1-2): 104-113

  Abstract

  An important question remains as to how the brain differentially processes first (pricking) pain mediated by Adelta-nociceptors versus second (burning) pain mediated by C-nociceptors. In the present cross-over randomized, within-subjects controlled study, brain activity patterns were examined with event-related fMRI while pricking and burning pain were selectively evoked using a diode laser. Stimuli evoking equivalent pain intensities were delivered to the dorsum of the left foot. Different laser parameters were used to elicit pricking (60ms pulse duration) and burning (2.0s pulse duration) pain. Whole brain group analysis showed that several brain areas were commonly activated by pricking and burning pain, including bilateral thalamus, bilateral anterior insula, bilateral posterior parietal lobule, contralateral dorsolateral prefrontal cortex, ipsilateral cerebellum, and mid anterior cingulate cortex. These findings show that pricking and burning pain were associated with activity in many of the same nociceptive processing brain regions. This may be expected given that Adelta-and C-nociceptive signals converge to a great extent at the level of the dorsal horn. Other brain regions showed differential processing. Stronger activation in the pricking pain condition was found in the ipsilateral hippocampus, bilateral parahippocampal gyrus, bilateral fusiform gyrus, contralateral cerebellum and contralateral cuneus/parieto-occipital sulcus. Stronger activation in the burning pain condition was found in the ipsilateral dorsolateral prefrontal cortex. These differential activation patterns suggest preferential importance of Adelta-fiber signals versus C-fiber signals for these specific brain regions.

  View details for DOI 10.1016/j.pain.2008.10.027

  View details for Web of Science ID 000263014400018

  View details for PubMedID 19058914

• Identifying biological markers of activity in human nociceptive pathways to facilitate analgesic drug development PAIN Chizh, B. A., Greenspan, J. D., Casey, K. L., Nemenov, M. I., Treede, R. 2008; 140 (2): 249-253

  View details for DOI 10.1016/j.pain.2008.09.024

  View details for Web of Science ID 000261551700002

  View details for PubMedID 18950938

• Non-invasive diode laser activation of transient receptor potential proteins in nociceptors. Proceedings - Society of Photo-Optical Instrumentation Engineers Jiang, N., Cooper, B. Y., Nemenov, M. I. 2007; 6428

  Abstract

  We investigated diode laser (980 nm) evoked activation of transient receptor potential proteins (TRPV1 and TRPV2). C and A-delta (Aδ) nociceptor families are primarily responsible for pain mediation in the peripheral nervous system. TRPV1 proteins have been associated with heat evoked pain in C fibers while Aδ fibers have been associated with TRPV2. Diode laser stimulation allows a margin of safety between non-invasive activation and damage (19, 22, 34). Laser pulses (20-50 ms, 0.1-10 W, 980 nm) were used to stimulate: A) in vitro: excised patches from HEK293 cells expressing TRPV1; B) in vitro: rat DRG nociceptors expressing either TRPV1 or TRPV2; and C) in vivo: C-fibers of the rat saphenous nerve (SN) trunk. Cell currents were recorded using standard patch clamp methods. The SN was also stimulated electrically with bipolar electrodes. Stimulation (20-50 ms) of HEK and DRG cells expressing TRPV1 was highly reproducible. Activation and peak currents were achieved at estimated peak temperatures of 55°C and 70°C. Threshold activation was also observed in DRG neurons expressing TRPV2. The conduction velocity for laser-activated saphenous nerve afferents was in the C fiber range (0.5-1 m/s). Electrically stimulated nerve contained stimulation artifacts and complex neural components with conduction velocities ranging from 0.3-30 m/s. Diode laser activation of TRPV1 protein is a reproducible and effective means to probe TRP activity in both in vivo and in vitro preparations.

  View details for DOI 10.1117/12.699204

  View details for PubMedID 21709727

  View details for PubMedCentralID PMC3122473

• Differential activation of trigeminal C or A delta nociceptors by infrared diode laser in rats: Behavioral evidence BRAIN RESEARCH Tzabazis, A., Klyukinov, M., Manering, N., Nemenov, M. I., Shafer, S. L., Yeomans, D. C. 2005; 1037 (1-2): 148-156

  Abstract

  Radiant heat is often used for studying thermal nociception, although inherent characteristics such as the broad spectrum of applied wavelengths of typical light sources limit control over and repeatability of stimuli. To overcome these problems, we used a diode infrared laser-based stimulator (wavelength: 980 nm) for selectively stimulating trigeminal Adelta or C thermonociceptors in rats. To provide indirect evidence for nociceptor-selective stimulation, we tested the effects of capsaicin, dimethylsulfoxide (DMSO), and morphine on withdrawal latencies for long pulses with a low current (hypothesized to selectively stimulate C nociceptors) and for threshold currents of short pulses with high current (hypothesized to selectively stimulate Adelta nociceptors) in lightly anesthetized rats. Nonmem analysis was used to perform pharmacodynamic modeling. The measured baseline withdrawal latency for long pulses was 12.5 +/- 0.3 s which was changed significantly to 6.7 +/- 0.4 s after applying topical capsaicin which selectively sensitizes C nociceptors and to 16.5 +/- 1.3 s after 1.0 mg/kg morphine which preferentially attenuates C fiber nociception. Topical DMSO which appears to selectively sensitize Adelta afferents did not significantly alter withdrawal latencies to the long pulses. Fitted threshold currents for short pulses after DMSO were however significantly lower (974 +/- 53 mA vs. 1113 +/- 12 mA for baseline) indicating Adelta sensitization. Capsaicin and morphine did not significantly change threshold currents. Best Nonmem fits for the long pulse were obtained using a model assuming no DMSO effect, but a different inter-individual variability after applying this substance. For the short pulse, a model assuming no capsaicin or morphine effect, but again allowing different inter-individual variabilities after applying these drugs, best described the data. We conclude that different settings of the stimulator used in this study were capable of selectively activating trigeminal Adelta or C thermonociceptors.

  View details for DOI 10.1016/j.brainres.2005.01.019

  View details for PubMedID 15777763

• Inward currents in primary nociceptive neurons of the rat and pain sensations in humans elicited by infrared diode laser pulses PAIN Greffrath, W., Nemenov, M. I., Schwarz, S., Baumgartner, U., Vogel, H., Arendt-Nielsen, L., Treede, R. D. 2002; 99 (1-2): 145-155

  Abstract

  Radiant heat is often used to study nociception in vivo. We now used infrared radiation generated by a diode laser stimulator (wavelength 980 nm) to investigate transduction mechanisms for noxious heat stimuli in acutely dissociated dorsal root ganglion (DRG) neurons of rats in vitro. The laser stimulator offered the unique opportunity to test whether the same stimuli also elicit pain sensations in humans. A specific heat-induced current (I(heat)) was elicited in six of 13 small DRG neurons (diameter < or =30 microm) tested in the whole-cell configuration of the patch-clamp mode. Current responses in the seven heat-insensitive neurons were within the range explainable by the temperature dependence of the recording setup. I(heat) was characterized by: (1) non-linearity of its amplitude during a suprathreshold heat ramp as well as with stimuli of increasing intensity with an estimated threshold of 42 +/- 1 degrees C; (2) fast rise time and even faster decay time (t(1/2) = 96.5 +/- 5.9 and 27.7 +/- 1.5 ms, respectively); and (3) rate dependence of its induction. All three heat-sensitive neurons tested were also sensitive to capsaicin. The mean threshold for the induction of I(heat) was 2.8 +/- 0.3 J mm(-2). The threshold for the induction of action potentials by depolarizing current pulses was significantly reduced after laser stimulation, suggesting a sensitization at the transformation stage. No such change was seen in heat-insensitive neurons that underwent the same heat stimuli. The same diode laser elicited pain sensations and laser-evoked potentials in human subjects. No significant differences were seen between the pain thresholds in hairy and in glabrous skin, probably due to the deep penetration of this laser radiation. The mean pain threshold for stimuli > or =200 ms in humans was 2.5 +/- 0.2 J mm(-2) (n = 11), and did not differ from the thresholds for the induction of I(heat) in vitro. Our results indicate that I(heat) in primary sensory neurons can be activated by infrared laser pulses that are painful in humans.

  View details for Web of Science ID 000178439800015

  View details for PubMedID 12237192

• Laser Radiation in Skin Sensitivity Research Journal of Sensory Systems Russian Academy of Sciences Tsirulnikov EM, Nemenov MI, Andreeeva IG 1997; 11 (2): 222-233
• Investigation of Skin Sensitivity Due To Visible and Near-Infrared Laser Radiation Biomedical Optical Instrumentation and Laser-Assisted Biotechnology, Proceedings of the NATO Advanced Study Institute, Erice, Italy, November 10-22, 1995: NATO Science Series E Nemenov MI, Tsirulnikov EM, Vekshin AA, Andreeva IG 1995; 325: 73-80
• Thermal And Skin Pain Sensations Due to Laser Irradiation SPIE Proceeding Nemenov MI, Gladysheva LG, Tsirulnikov EM, Andreeva IG 1995; 2323b: 537-38
• Laser irradiation influence on skin sensitivity edited by Shladov, I., Weissman, Y., Kopeika, N. 1995: 38–40

  View details for DOI 10.1117/12.211224

• THERMAL AND SKIN PAIN SENSATIONS DUE TO LASER IRRADIATION Conference on Laser Interaction with Hard and Soft tissue II Nemenov, M. I. 1995: 537–38
• THERMAL AND SKIN PAIN SENSATIONS DUE TO LASER IRRADIATION Conference on Laser Interaction with Hard and Soft tissue II Nemenov, M. I., GLADYSHEVA, L. G., TSIRULNIKOV, E. M., Andreeva, I. G. SPIE - INT SOC OPTICAL ENGINEERING. 1995: 537–538

  View details for Web of Science ID A1995BC34Q00063