Maximum axonal following frequency separates classes of cutaneous unmyelinated nociceptors in the pig.

KEY POINTS: C-nociceptors are generally assumed to have a low maximum discharge frequency of 10-30 Hz. However, only mechano-insensitive 'silent' C-nociceptors cannot follow electrical stimulation at 5 Hz (75 pulses) whereas polymodal C-nociceptors in the pig follow stimulation at up to 100 Hz without conduction failure. Sensitization by nerve growth factor increases the maximum following frequency of 'silent' nociceptors in pig skin and might thereby contribute in particular to intense pain sensations in chronic inflammation. A distinct class of C-nociceptors with mechanical thresholds >150 mN resembles 'silent' nociceptors at low stimulation frequencies in pigs and humans, but is capable of 100 Hz discharge and thus is suited to encode painfulness of noxious mechanical stimuli. ABSTRACT: Using extracellular single-fibre recordings from the saphenous nerve in pig in vivo, we investigated peak following frequencies (5-100 Hz) in different classes of C-nociceptors and their modulation by nerve growth factor. Classes were defined by sensory (mechano-sensitivity) and axonal characteristics (activity dependent slowing of conduction, ADS). Mechano-insensitive C-nociceptors (CMi) showed the highest ADS (34% ± 8%), followed only 66% ± 27% of 75 pulses at 5 Hz and increasingly blocked conduction at higher frequencies. Three weeks following intradermal injections of nerve growth factor, peak following frequency increased specifically in the sensitized mechano-insensitive nociceptors (20% ± 16% to 38% ± 23% response rate after 72 pulses at 100 Hz). In contrast, untreated polymodal nociceptors with moderate ADS (15.2% ± 10.2%) followed stimulation frequencies of 100 Hz without conduction failure (98.5% ± 6%). A distinct class of C-nociceptors was exclusively sensitive to strong forces above 150 mN. This class had a high ADS (27.2% ± 7.6%), but displayed almost no propagation failure even at 100 Hz stimulation (84.7% ± 17%). Also, among human mechanosensitive nociceptors (n = 153) those with thresholds above 150 mN (n = 5) showed ADS typical of silent nociceptors. C-fibres with particularly high mechanical thresholds and high following frequency form a distinct nociceptor class ideally suited to encode noxious mechanical stimulation under normal conditions when regular silent nociceptors are inactive. Sensitization by nerve growth factor increases maximum discharge frequency of silent nociceptors, thereby increasing the frequency range beyond their physiological limit, which possibly contributes to excruciating pain under inflammatory conditions.

Artifact reduction by using alternating polarity stimulus pairs in intraoperative peripheral nerve action potential recording.

Intraoperative nerve action potential (NAP) recording permits direct study of an injured nerve for functional assessment of lesions in continuity. Stimulus artifact contamination often hampers NAP recording and interferes with its interpretation. In the present study, we evaluated the artifact reduction method using alternating polarity in peripheral nerve recording. Our study was conducted under controlled conditions in laboratory animals. NAPs were recorded from surgically exposed median or ulnar nerves. For the artifact reduction method with alternating polarity, two sequential recordings, one with normal and one with reversed stimulus polarity, were acquired and the signals from this recording pair were averaged. Simulation was also performed to further evaluate the effects of alternating polarity on the waveforms. The results are as follows: First, we found that this method worked for recordings with unsaturated electrical stimulus artifacts. Second, slightly unequal latencies occurred in an NAP pair, and this inequality contributed to a minimal loss of NAP amplitudes when averaging the two recordings. Third, perfect artifact cancelation and minimal signal loss were also demonstrated by simulation. Finally, we applied the method during nerve inching and demonstrated its usefulness in intraoperative NAP recordings as the method made the recording more resilient to short conduction distances. Thus, our findings demonstrate that this artifact reduction method can be used as a supplemental tool together with our previously described bridge grounding technique or the nonlifting nerve recording configuration to further improve intraoperative peripheral nerve recording. The method can be applied in clinical settings.

Sensory neurons and circuits mediating itch.

Chemicals that are used experimentally to evoke itch elicit activity in diverse subpopulations of cutaneous pruriceptive neurons, all of which also respond to painful stimuli. However, itch is distinct from pain: it evokes different behaviours, such as scratching, and originates from the skin or certain mucosae but not from muscle, joints or viscera. New insights regarding the neurons that mediate the sensation of itch have been gained from experiments in which gene expression has been manipulated in different types of pruriceptive neurons as well as from comparisons between psychophysical measurements of itch and the neuronal discharges and other properties of peripheral and central pruriceptive neurons.

Sodium Channel Nav1.8 Underlies TTX-Resistant Axonal Action Potential Conduction in Somatosensory C-Fibers of Distal Cutaneous Nerves.

Voltage-gated sodium (NaV) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine NaV channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (NaV1.1-NaV1.4, NaV1.6-NaV1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (NaV1.8 and NaV1.9) inhibited by millimolar concentrations, with NaV1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different NaV channel isoforms are distributed along the peripheral and central branches of their bifurcated axons. To determine the relative contribution of TTX-s and TTX-r channels to action potential conduction in different axonal compartments, we investigated the effects of TTX on C-fiber-mediated compound action potentials (C-CAPs) of proximal and distal peripheral nerve segments and dorsal roots from mice and pigtail monkeys (Macaca nemestrina). In the dorsal roots and proximal peripheral nerves of mice and nonhuman primates, TTX reduced the C-CAP amplitude to 16% of the baseline. In contrast, >30% of the C-CAP was resistant to TTX in distal peripheral branches of monkeys and WT and NaV1.9-/- mice. In nerves from NaV1.8-/- mice, TTX-r C-CAPs could not be detected. These data indicate that NaV1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of NaV1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of NaV1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin.SIGNIFICANCE STATEMENT It is unclear whether individual sodium channel isoforms exert differential roles in action potential conduction along the axonal membrane of nociceptive, unmyelinated peripheral nerve fibers, but clarifying the role of sodium channel subtypes in different axonal segments may be useful for the development of novel analgesic strategies. Here, we provide evidence from mice and nonhuman primates that a substantial portion of the C-fiber compound action potential in distal peripheral nerves, but not proximal nerves or dorsal roots, is resistant to tetrodotoxin and that, in mice, this effect is mediated solely by voltage-gated sodium channel 1.8 (NaV1.8). The functional prominence of NaV1.8 within the axonal compartment immediately proximal to its termination may affect strategies targeting pain of peripheral origin.

Overexpression of µ-Opioid Receptors in Peripheral Afferents, but Not in Combination with Enkephalin, Decreases Neuropathic Pain Behavior and Enhances Opioid Analgesia in Mouse.

BACKGROUND: The current study used recombinant herpes simplex virus type I to increase expression of µ-opiate receptors and the opioid ligand preproenkephalin in peripheral nerve fibers in a mouse model of neuropathic pain. It was predicted that viral vector delivery of a combination of genes encoding the µ-opioid receptor and preproenkephalin would attenuate neuropathic pain and enhance opioid analgesia. The behavioral effects would be paralleled by changes in response properties of primary afferent neurons. METHODS: Recombinant herpes simplex virus type 1 containing cDNA sequences of the µ-opioid receptor, human preproenkephalin, a combination, or Escherichia coli lacZ gene marker (as a control) was used to investigate the role of peripheral opioids in neuropathic pain behaviors. RESULTS: Inoculation with the µ-opioid receptor viral vector (n = 13) reversed mechanical allodynia and thermal hyperalgesia and produced leftward shifts in loperamide (ED50 = 0.6 ± 0.2 mg/kg vs. ED50 = 0.9 ± 0.2 mg/kg for control group, n = 8, means ± SD) and morphine dose-response curves (ED50 = 0.3 ± 0.5 mg/kg vs. ED50 = 1.1 ± 0.1 mg/kg for control group). In µ-opioid receptor viral vector inoculated C-fibers, heat-evoked responses (n = 12) and ongoing spontaneous activity (n = 18) were decreased after morphine application. Inoculation with both µ-opioid receptor and preproenkephalin viral vectors did not alter mechanical and thermal responses. CONCLUSIONS: Increasing primary afferent expression of opioid receptors can decrease neuropathic pain-associated behaviors and increase systemic opioid analgesia through inhibition of peripheral afferent fiber activity.

Enhanced sodium channel inactivation by temperature and FHF2 deficiency blocks heat nociception.

ABSTRACT: Transient voltage-gated sodium currents are essential for the initiation and conduction of action potentials in neurons and cardiomyocytes. The amplitude and duration of sodium currents are tuned by intracellular fibroblast growth factor homologous factors (FHFs/iFGFs) that associate with the cytoplasmic tails of voltage-gated sodium channels (Na v s), and genetic ablation of Fhf genes disturbs neurological and cardiac functions. Among reported phenotypes, Fhf2null mice undergo lethal hyperthermia-induced cardiac conduction block attributable to the combined effects of FHF2 deficiency and elevated temperature on the cardiac sodium channel (Na v 1.5) inactivation rate. Fhf2null mice also display a lack of heat nociception, while retaining other somatosensory capabilities. Here, we use electrophysiological and computational methods to show that the heat nociception deficit can be explained by the combined effects of elevated temperature and FHF2 deficiency on the fast inactivation gating of Na v 1.7 and tetrodotoxin-resistant sodium channels expressed in dorsal root ganglion C fibers. Hence, neurological and cardiac heat-associated deficits in Fhf2null mice derive from shared impacts of FHF deficiency and temperature towards Na v inactivation gating kinetics in distinct tissues.

A role for nociceptive, myelinated nerve fibers in itch sensation.

Despite its clinical importance, the underlying neural mechanisms of itch sensation are poorly understood. In many diseases, pruritus is not effectively treated with antihistamines, indicating the involvement of nonhistaminergic mechanisms. To investigate the role of small myelinated afferents in nonhistaminergic itch, we tested, in psychophysical studies in humans, the effect of a differential nerve block on itch produced by intradermal insertion of spicules from the pods of a cowhage plant (Mucuna pruriens). Electrophysiological experiments in anesthetized monkey were used to investigate the responsiveness of cutaneous, nociceptive, myelinated afferents to different chemical stimuli (cowhage spicules, histamine, capsaicin). Our results provide several lines of evidence for an important role of myelinated fibers in cowhage-induced itch: (1) a selective conduction block in myelinated fibers substantially reduces itch in a subgroup of subjects with A-fiber-dominated itch, (2) the time course of itch sensation differs between subjects with A-fiber- versus C-fiber-dominated itch, (3) cowhage activates a subpopulation of myelinated and unmyelinated afferents in monkey, (4) the time course of the response to cowhage is different in myelinated and unmyelinated fibers, (5) the time of peak itch sensation for subjects with A-fiber-dominated itch matches the time for peak response in myelinated fibers, and (6) the time for peak itch sensation for subjects with C-fiber-dominated itch matches the time for the peak response in unmyelinated fibers. These findings demonstrate that activity in nociceptive, myelinated afferents contributes to cowhage-induced sensations, and that nonhistaminergic itch is mediated through activity in both unmyelinated and myelinated afferents.

Macrophage-mediated dorsal root ganglion damage precedes altered nerve conduction in SIV-infected macaques.

Peripheral neuropathy is the most common neurological complication of HIV-1 infection, affecting over one-third of infected individuals, including those treated with antiretroviral therapy. To study the pathogenesis of HIV-induced peripheral nervous system disease, we established a model in which SIV-infected macaques developed changes closely resembling alterations reported in components of the sensory pathway in HIV-infected individuals. Significant declines in epidermal nerve fiber density developed in SIV-infected macaques, similar to that of HIV-infected individuals with neuropathy. Changes in dorsal root ganglia (DRG) included macrophage infiltration, SIV replication in macrophages, immune activation of satellite cells, and neuronal loss. To determine whether dorsal root ganglion damage was associated with altered nerve function, we measured unmyelinated C-fiber conduction velocities (CV) in nerves of SIV-infected macaques and compared CV changes with DRG alterations. Twelve weeks postinoculation, SIV-infected macaques had significantly lower C-fiber conduction velocity in sural nerves than uninfected animals and the magnitude of conduction velocity decline correlated strongly with extent of DRG macrophage infiltration. Thus, injury to neurons in the DRG-mediated by activated macrophages-preceded altered conduction of unmyelinated nerve fibers in SIV-infected macaques, suggesting that macrophage-mediated DRG damage may be the initiating event in HIV-induced sensory neuropathy.

The differential effects of two sodium channel modulators on the conductive properties of C-fibers in pig skin in vivo.

BACKGROUND: Axonal sodium channels are attractive targets for chronic pain treatment, and recent evidence suggests that specific targeting of the slow inactivation of sodium channels (NaV) might exert analgesic effects. Using a human-like animal model, the pig, we compared changes in the conductive properties of different C-fiber classes on acute administration of lidocaine (nonselective NaV blocker) and lacosamide (selective enhancer of NaV slow inactivation). METHODS: Single-fiber extracellular recordings from saphenous nerves were performed. We classified C-fibers according to mechanical responsiveness and amount of activity-dependent slowing (ADS) of conduction velocity. Lidocaine (4 mM; 100 µL), lacosamide (4 mM; 100 µL), or saline was injected intradermally at the stimulation site, and changes of fibers' conductive properties were assessed. RESULTS: Conduction latencies evoked by lidocaine were more prominent in mechanosensitive (5.5%± 2.1%) than in mechano-insensitive nociceptors (2.5% ± 1%), whereas lacosamide increased conduction latencies to a greater extent in the mechano-insensitive (3% ± 1%) than in mechanosensitive C-nociceptors (2% ± 0.9%). Lidocaine, but not lacosamide, increased electrical thresholds in all mechanosensitive, but not in the mechano-insensitive, C-fibers. Lacosamide blocked conduction and, in addition, reduced ADS in mechano-insensitive nociceptors significantly more than in mechanosensitive nociceptors (ΔADS: 2.4% ± 0.5% vs 1.6% ± 0.5%), whereas lidocaine had opposite effects. Saline had no significant effect on the conductive properties of C-fibers. CONCLUSION: Local application of test compounds in pig skin allows for functional assessment of steady-state and use-dependent modulation of sodium channels in nociceptive and nonnociceptive C-fibers. Increased analgesic specificity might derive from selective enhancement of slow inactivation of sodium channels.

Pruriception and neuronal coding in nociceptor subtypes in human and nonhuman primates.

In humans, intradermal administration of ß-alanine (ALA) and bovine adrenal medulla peptide 8-22 (BAM8-22) evokes the sensation of itch. Currently, it is unknown which human dorsal root ganglion (DRG) neurons express the receptors of these pruritogens, MRGPRD and MRGPRX1, respectively, and which cutaneous afferents these pruritogens activate in primate. In situ hybridization studies revealed that MRGPRD and MRGPRX1 are co-expressed in a subpopulation of TRPV1+ human DRG neurons. In electrophysiological recordings in nonhuman primates (Macaca nemestrina), subtypes of polymodal C-fiber nociceptors are preferentially activated by ALA and BAM8-22, with significant overlap. When pruritogens ALA, BAM8-22, and histamine, which activate different subclasses of C-fiber afferents, are administered in combination, human volunteers report itch and nociceptive sensations similar to those induced by a single pruritogen. Our results provide evidence for differences in pruriceptive processing between primates and rodents, and do not support the spatial contrast theory of coding of itch and pain.

Peripheral Sensitization and Loss of Descending Inhibition Is a Hallmark of Chronic Pruritus.

Neurophysiological mechanisms leading to chronicity of pruritus are not yet fully understood and it is not known whether these mechanisms diverge between different underlying diseases of chronic pruritus (CP). This study aimed to detect such mechanisms in CP of various origins. A total of 120 patients with CP of inflammatory origin (atopic dermatitis), neuropathic origin (brachioradial pruritus), and chronic prurigo of nodular type, the latter as a model for chronic scratching, as well as 40 matched healthy controls participated in this study. Stimulation with cowhage induced a more intensive itch sensation compared with stimulation with other substances in all patient groups but not in healthy controls, arguing for sensitization of cutaneous mechano- and heat-sensitive C-fibers in CP. All patient groups showed a decreased intraepidermal nerve fiber density compared with controls. A decreased condition pain modulation effect was observed in all patient groups compared with controls, suggesting a reduced descending inhibitory system in CP. In sum, CP of different etiologies showed a mixed peripheral and central pattern of neuronal alterations, which might contribute to the chronicity of pruritus with no differences between pruritus entities. Our findings may contribute to the development of future treatment strategies targeting these pathomechanisms.

The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises.

ABSTRACT: The current International Association for the Study of Pain (IASP) definition of pain as "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" was recommended by the Subcommittee on Taxonomy and adopted by the IASP Council in 1979. This definition has become accepted widely by health care professionals and researchers in the pain field and adopted by several professional, governmental, and nongovernmental organizations, including the World Health Organization. In recent years, some in the field have reasoned that advances in our understanding of pain warrant a reevaluation of the definition and have proposed modifications. Therefore, in 2018, the IASP formed a 14-member, multinational Presidential Task Force comprising individuals with broad expertise in clinical and basic science related to pain, to evaluate the current definition and accompanying note and recommend whether they should be retained or changed. This review provides a synopsis of the critical concepts, the analysis of comments from the IASP membership and public, and the committee's final recommendations for revisions to the definition and notes, which were discussed over a 2-year period. The task force ultimately recommended that the definition of pain be revised to "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage," and that the accompanying notes be updated to a bulleted list that included the etymology. The revised definition and notes were unanimously accepted by the IASP Council early this year.

A role for polymodal C-fiber afferents in nonhistaminergic itch.

Recent psychophysical and electrophysiological studies in humans suggest the existence of two peripheral pathways for itch, one that is responsive to histamine and a second pathway that can be activated by nonhistaminergic pruritogens (e.g., cowhage spicules). To explore the peripheral neuronal pathway for nonhistaminergic itch, behavioral responses and neuronal activity in unmyelinated afferent fibers were assessed in monkey after topical application of cowhage spicules or intradermal injection of histamine and capsaicin. Cowhage and histamine, but not capsaicin, evoked scratching behavior indicating the presence of itch. In single-fiber recordings, cowhage, histamine and/or capsaicin were applied to the cutaneous receptive field of 43 mechano-heat-sensitive C-fiber (CMH) nociceptors. The majority of CMHs exhibited a prolonged response to cowhage (39 of 43) or histamine (29 of 38), but not to capsaicin (3 of 34). Seven CMHs were activated by cowhage but not histamine. The average response to cowhage was more than twice the response to histamine, and responses were not correlated. The response of the CMHs to a stepped heat stimulus (49 degrees C, 3 s) was either quickly adapting (QC) or slowly adapting (SC). In contrast, the cowhage response was characterized by bursts of two or more action potentials (at approximately 1 Hz). The total cowhage response of the QC fibers (97 action potentials/5 min) was twice that of the SC fibers (49 action potentials/5 min). A subset of QC fibers exhibited high-frequency intraburst discharges ( approximately 30 Hz). These results suggest multiple mechanisms by which CMHs may encode itch to cowhage as well as pain to mechanical and heat stimuli.

Thermoreceptors and thermosensitive afferents.

Cutaneous thermosensation plays an important role in thermal regulation and detection of potentially harmful thermal stimuli. Multiple classes of primary afferents are responsive to thermal stimuli. Afferent nerve fibers mediating the sensation of non-painful warmth or cold seem adapted to convey thermal information over a particular temperature range. In contrast, nociceptive afferents are often activated by both, painful cold and heat stimuli. The transduction mechanisms engaged by thermal stimuli have only recently been discovered. Transient receptor potential (TRP) ion channels that can be activated by temperatures over specific ranges potentially provide the molecular basis for thermosensation. However, non-TRP mechanisms are also likely to contribute to the transduction of thermal stimuli. This review summarizes findings regarding the transduction proteins and the primary afferents activated by innocuous and noxious cold and heat.

Solutions to the technical challenges embedded in the current methods for intraoperative peripheral nerve action potential recordings.

OBJECTIVE: Intraoperative nerve action potential (NAP) recording is a useful tool for surgeons to guide decisions on surgical approaches during nerve repair surgeries. However, current methods remain technically challenging. In particular, stimulus artifacts that contaminate or mask the NAP and therefore impair the interpretation of the recording are a common problem. The authors' goal was to improve intraoperative NAP recording techniques by revisiting the methods in an experimental setting. METHODS: First, NAPs were recorded from surgically exposed peripheral nerves in monkeys. For the authors to test their assumptions about observed artifacts, they then employed a simple model system. Finally, they applied their insights to clinical cases in the operating room. RESULTS: In monkey peripheral nerve recordings, large stimulus artifacts obscured NAPs every time the nerve segment (length 3-5 cm) was lifted up from the surrounding tissue, and NAPs could not be recorded. Artifacts were suppressed, and NAPs emerged when "bridge grounding" was applied, and this allowed the NAPs to be recorded easily and reliably. Tests in a model system suggested that exaggerated stimulus artifacts and unmasking of NAPs by bridge grounding are related to a loop effect that is created by lifting the nerve. Consequently, clean NAPs were acquired in "nonlifting" recordings from monkey peripheral nerves. In clinical cases, bridge grounding efficiently unmasked intraoperative NAP recordings, validating the authors' principal concept in the clinical setting and allowing effective neurophysiological testing in the operating room. CONCLUSIONS: Technical challenges of intraoperative NAP recording are embedded in the current methods that recommend lifting the nerve from the tissue bed, thereby exaggerating stimulus artifacts by a loop effect. Better results can be achieved by performing nonlifting nerve recording or by applying bridge grounding. The authors not only tested their findings in an animal model but also applied them successfully in clinical practice.

Psychophysical and physiological evidence for parallel afferent pathways mediating the sensation of itch.

The neuronal pathways for itch have been characterized mainly based on responses to histamine. Intracutaneous application of histamine produces intense itch and a large area of axon-reflexive vasodilation ("flare") around the application site. Both phenomena are thought to be mediated through neuronal activity in itch-specific, mechanoinsensitive C-fiber afferents (CMi). However, mechanical and electrical stimuli that do not activate CMi fibers can cause the sensation of itch, and itch may occur without flare, suggesting that other neuronal itch pathways exist. Because cutaneous application of spicules from the plant Mucuna pruriens (cowhage) has been anecdotally reported to produce itch without flare, we performed psychophysical experiments to investigate whether the mechanisms underlying cowhage- and histamine-induced itch differ. Although histamine and cowhage produced itch of similar magnitude, the itch to cowhage was not correlated with the itch to histamine; some subjects had intense itch to cowhage and little itch to histamine and visa versa. Laser Doppler measurements of blood flow revealed that histamine led to a large area of vasodilation, whereas cowhage produced vasodilation restricted to the application site. Pretreatment of the skin with an antihistamine blocked the itch produced by histamine but did not prevent cowhage-induced itch. Desensitization of the skin with topical capsaicin abolished cowhage-induced itch but did not significantly alter histamine-induced itch. These findings indicate that cowhage itch is signaled through a population of capsaicin-sensitive afferent nerve fibers that is distinct from CMi fibers mediating histamine-induced itch. Cowhage may be useful to investigate the neural pathway mediating nonhistaminergic itch.

A role for uninjured afferents in neuropathic pain.

Diseases and injuries to the nervous system can lead to a devastating chronic pain condition called neuropathic pain. We review changes that occur in the peripheral nervous system that may play a role in this disease. Common animal models for neuropathic pain involve an injury to one or more peripheral nerves. Following such an injury, the nerve fibers that have been injured exhibit many abnormal properties including the development of spontaneous neural activity as well as a change in the expression of certain genes in their cell body. Recent data indicate that adjacent, uninjured nerve fibers also exhibit significant changes. These changes are thought to be driven by injury-induced alterations in the milieu surrounding the uninjured nerve and nerve terminals. Thus, alteration in neural signaling in both injured and uninjured neurons play a role in the development of neuropathic pain after peripheral nerve injury.

Lumbar sympathectomy attenuates cold allodynia but not mechanical allodynia and hyperalgesia in rats with spared nerve injury.

UNLABELLED: In certain patients with neuropathic pain, the pain is dependent on activity in the sympathetic nervous system. To investigate whether the spared nerve injury model (SNI) produced by injury to the tibial and common peroneal nerves and leaving the sural nerve intact is a model for sympathetically maintained pain, we measured the effects of surgical sympathectomy on the resulting mechanical allodynia, mechanical hyperalgesia, and cold allodynia. Decreases of paw withdrawal thresholds to von Frey filament stimuli and increases in duration of paw withdrawal to pinprick or acetone stimuli were observed in the ipsilateral paw after SNI, compared with their pre-SNI baselines. Compared with sham surgery, surgical lumbar sympathectomy had no effect on the mechanical allodynia and mechanical hyperalgesia induced by SNI. However, the sympathectomy significantly attenuated the cold allodynia induced by SNI. These results suggest that the allodynia and hyperalgesia to mechanical stimuli in the SNI model is not sympathetically maintained. However, the sympathetic nervous system may be involved, in part, in the mechanisms of cold allodynia in the SNI model. PERSPECTIVE: The results of our study suggest that the SNI model is not an appropriate model of sympathetically maintained mechanical allodynia and hyperalgesia but may be useful to study the mechanisms of cold allodynia associated with sympathetically maintained pain states.

Laser speckle imaging to improve clinical outcomes for patients with trigeminal neuralgia undergoing radiofrequency thermocoagulation.

OBJECTIVE: Percutaneous treatments for trigeminal neuralgia are safe, simple, and effective for achieving good pain control. Procedural risks could be minimized by using noninvasive imaging techniques to improve the placement of the radiofrequency thermocoagulation probe into the trigeminal ganglion. Positioning of a probe is crucial to maximize pain relief and to minimize unwanted side effects, such as denervation in unaffected areas. This investigation examined the use of laser speckle imaging during probe placement in an animal model. METHODS: This preclinical safety study used nonhuman primates, Macaca nemestrina (pigtail monkeys), to examine whether real-time imaging of blood flow in the face during the positioning of a coagulation probe could monitor the location and guide the positioning of the probe within the trigeminal ganglion. RESULTS: Data from 6 experiments in 3 pigtail monkeys support the hypothesis that laser imaging is safe and improves the accuracy of probe placement. CONCLUSIONS: Noninvasive laser speckle imaging can be performed safely in nonhuman primates. Because improved probe placement may reduce morbidity associated with percutaneous rhizotomies, efficacy trials of laser speckle imaging should be conducted in humans.

Fatigue and paradoxical enhancement of heat response in C-fiber nociceptors from cross-modal excitation.

Fatigue refers to the decrement of response seen with repeated stimulation and is a prominent attribute of nociceptors. Whether fatigue in nociceptors involves transduction, spike initiation, or conduction mechanisms is unknown. We investigated systematically how electrical, mechanical, and heat conditioning stimuli (eCS, mCS, hCS) affected the subsequent response to a test-heat stimulus applied 5 sec later to the receptive field of cutaneous nociceptors. Standard teased-fiber techniques were used to record from mechano-heat-sensitive C-fiber afferents in the anesthetized monkey. The eCS was applied to the nerve trunk, whereas the hCS and mCS were applied to the heat-test site. For the eCS, the number of pulses rather than frequency of stimulation determined the level of fatigue. Fatigue varied inversely with the time interval between the eCS and the test stimulus. For comparable responses from the CS, the magnitude of fatigue was less after the mCS than after the eCS. The mCS (but not the eCS) sometimes evoked a paradoxical increase in response to the test-heat stimulus. Recovery from fatigue was significantly faster after the eCS and mCS than the hCS. The paradoxical enhancement after the mCS probably results from temporal summation of generator potentials produced by mechanical and heat stimulation and suggests that the time constant of the generator potential is on the order of seconds. Concurrent enhancement-fatigue effects may also explain why fatigue was less after the mCS than the eCS. The dependency of recovery from fatigue on the modality of the CS suggests that fatigue results from transduction-spike initiation mechanisms.