In primates, C-fibre polymodal nociceptors are broadly classified into two groups based on mechanosensitivity. Here we demonstrate that mechanically sensitive polymodal nociceptors that respond either quickly (QC) or slowly (SC) to a heat stimulus differ in responses to a mild burn, heat sensitization, conductive properties and chemosensitivity. Superficially applied capsaicin and intradermal injection of β-alanine, an MrgprD agonist, excite vigorously all QCs. Only 40% of SCs respond to β-alanine, and their response is only half that of QCs. Mechanically insensitive C-fibres (C-MIAs) are β-alanine insensitive but vigorously respond to capsaicin and histamine with distinct discharge patterns. Calcium imaging reveals that β-alanine and histamine activate distinct populations of capsaicin-responsive neurons in primate dorsal root ganglion. We suggest that histamine itch and capsaicin pain are peripherally encoded in C-MIAs, and that primate polymodal nociceptive afferents form three functionally distinct subpopulations with β-alanine responsive QC fibres likely corresponding to murine MrgprD-expressing, non-peptidergic nociceptive afferents.

BACKGROUND:Spinal cord stimulation (SCS) is a useful neuromodulatory technique for treatment of certain neuropathic pain conditions. However, the optimal stimulation parameters remain unclear. METHODS:In rats after L5 spinal nerve ligation, the authors compared the inhibitory effects on mechanical hypersensitivity from bipolar SCS of different intensities (20, 40, and 80% motor threshold) and frequencies (50, 1 kHz, and 10 kHz). The authors then compared the effects of 1 and 50 Hz dorsal column stimulation at high- and low-stimulus intensities on conduction properties of afferent Aα/β-fibers and spinal wide-dynamic-range neuronal excitability. RESULTS:Three consecutive daily SCS at different frequencies progressively inhibited mechanical hypersensitivity in an intensity-dependent manner. At 80% motor threshold, the ipsilateral paw withdrawal threshold (% preinjury) increased significantly from pre-SCS measures, beginning with the first day of SCS at the frequencies of 1 kHz (50.2 ± 5.7% from 23.9 ± 2.6%, n = 19, mean ± SEM) and 10 kHz (50.8 ± 4.4% from 27.9 ± 2.3%, n = 17), whereas it was significantly increased beginning on the second day in the 50 Hz group (38.9 ± 4.6% from 23.8 ± 2.1%, n = 17). At high intensity, both 1 and 50 Hz dorsal column stimulation reduced Aα/β-compound action potential size recorded at the sciatic nerve, but only 1 kHz stimulation was partially effective at the lower intensity. The number of actions potentials in C-fiber component of wide-dynamic-range neuronal response to windup-inducing stimulation was significantly decreased after 50 Hz (147.4 ± 23.6 from 228.1 ± 39.0, n = 13), but not 1 kHz (n = 15), dorsal column stimulation. CONCLUSIONS:Kilohertz SCS attenuated mechanical hypersensitivity in a time course and amplitude that differed from conventional 50 Hz SCS, and may involve different peripheral and spinal segmental mechanisms.

Loperamide reverses signs of mechanical hypersensitivity in an animal model of neuropathic pain suggesting that peripheral opioid receptors may be suitable targets for the treatment of neuropathic pain. Since little is known about loperamide effects on the responsiveness of primary afferent nerve fibers, in vivo electrophysiological recordings from unmyelinated afferents innervating the glabrous skin of the hind paw were performed in rats with an L5 spinal nerve lesion or sham surgery. Mechanical threshold and responsiveness to suprathreshold stimulation were tested before and after loperamide (1.25, 2.5 and 5 µg in 10 µl) or vehicle injection into the cutaneous receptive field. Loperamide dose-dependently decreased mechanosensitivity in unmyelinated afferents of nerve-injured and sham animals, and this effect was not blocked by naloxone pretreatment. We then investigated loperamide effects on nerve conduction by recording compound action potentials in vitro during incubation of the sciatic nerve with increasing loperamide concentrations. Loperamide dose-dependently decreased compound action potentials of myelinated and unmyelinated fibers (ED50 = 8 and 4 µg/10 µl, respectively). This blockade was not prevented by pre-incubation with naloxone. These results suggest that loperamide reversal of behavioral signs of neuropathic pain may be mediated, at least in part, by mechanisms independent of opioid receptors, most probably by local anesthetic actions.

Spinal cord stimulation (SCS) is used clinically to treat neuropathic pain states, but the precise mechanism by which it attenuates neuropathic pain remains to be established. The profile of afferent fiber activation during SCS and how it may correlate with the efficacy of SCS-induced analgesia are unclear. After subjecting rats to an L5 spinal nerve ligation (SNL), we implanted a miniature quadripolar electrode similar to that used clinically. Our goal was to determine the population and number of afferent fibers retrogradely activated by SCS in SNL rats by recording the antidromic compound action potential (AP) at the sciatic nerve after examining the ability of bipolar epidural SCS to alleviate mechanical hypersensitivity in this model. Notably, we compared the profiles of afferent fiber activation to SCS between SNL rats that exhibited good SCS-induced analgesia (responders) and those that did not (nonresponders). Additionally, we examined how different contact configurations affect the motor threshold (MoT) and compound AP threshold. Results showed that three consecutive days of SCS treatment (50 Hz, 0.2 ms, 30 min, 80-90% of MoT), but not sham stimulation, gradually alleviated mechanical hypersensitivity in SNL rats. The MoT obtained in the animal behavioral study was significantly less than the Aα/β-threshold of the compound AP determined during electrophysiological recording, suggesting that SCS could attenuate mechanical hypersensitivity with a stimulus intensity that recruits only a small fraction of the A-fiber population in SNL rats. Although both the MoT and compound AP threshold were similar between responders and nonresponders, the size of the compound AP waveform at higher stimulation intensities was larger in the responders, indicating a more efficient activation of the dorsal column structure in responders.

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.

The neurophysiological basis by which neuromodulatory techniques lead to relief of neuropathic pain remains unclear. We investigated whether electrical stimulation at different peripheral sites induces unique profiles of A-fiber afferent activation in nerve-injured rats. At 4-6 weeks after subjecting rats to L5 spinal nerve injury (SNL) or sham operation, we recorded the orthodromic compound action potential (AP) at the ipsilateral L4 dorsal root in response to (1) transcutaneous electrical nerve stimulation (TENS, a patch electrode placed on the dorsum of the foot), (2) subcutaneous electrical stimulation (SQS, electrode inserted subcutaneously along the dorsum of the foot), (3) peroneal nerve stimulation (PNS, electrode placed longitudinally abutting the nerve), and (4) sciatic nerve stimulation (SNS). The area under the A alpha/beta compound AP was measured as a function of the bipolar, constant-current stimulus intensity (0.02-6.0 mA, 0.2 ms). In both nerve-injured and sham-operated groups, the stimulus-response (S-R) functions of the A alpha/beta compound APs differed substantially with the stimulation site; SNS having the lowest threshold and largest compound AP waveform, followed by PNS, SQS, and TENS. The S-R function to PNS was shifted to the right in the SNL group, compared to that in the sham-operated group. The A alpha/beta-threshold to PNS was higher in the SNL group than in the sham-operated group. The S-R functions and A alpha/beta-thresholds to TENS and SQS were comparable between the two groups. Electrical stimulation of different peripheral targets induced distinctive profiles of A-fiber afferent activation, suggesting that the neuronal substrates for the various forms of peripheral neuromodulatory therapies may differ. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

European Journal of Pain SupplementsVolume 5, Issue S1 p. 286-287 S704 PROPORTION OF MYELINATED FIBERS ACTIVATED BY VARIOUS PERIPHERAL TISSUE/NERVE ELECTRICAL STIMULATION THERAPIES DIFFER IN SPINAL NERVE-INJURED RATS P.W. Wacnik, P.W. Wacnik Neuromodulation Research, Medtronic, Minneapolis, MNSearch for more papers by this authorF. Yang, F. Yang Anesthesiology and Critical Care MedicineSearch for more papers by this authorC.-Y. Chung, C.-Y. Chung Anesthesiology and Critical Care MedicineSearch for more papers by this authorR.A. Meyer, R.A. Meyer Neurosurgery, Johns Hopkins University, Baltimore, MD, USASearch for more papers by this authorS.N. Raja, S.N. Raja Anesthesiology and Critical Care MedicineSearch for more papers by this authorY. Guan, Y. Guan Anesthesiology and Critical Care MedicineSearch for more papers by this author P.W. Wacnik, P.W. Wacnik Neuromodulation Research, Medtronic, Minneapolis, MNSearch for more papers by this authorF. Yang, F. Yang Anesthesiology and Critical Care MedicineSearch for more papers by this authorC.-Y. Chung, C.-Y. Chung Anesthesiology and Critical Care MedicineSearch for more papers by this authorR.A. Meyer, R.A. Meyer Neurosurgery, Johns Hopkins University, Baltimore, MD, USASearch for more papers by this authorS.N. Raja, S.N. Raja Anesthesiology and Critical Care MedicineSearch for more papers by this authorY. Guan, Y. Guan Anesthesiology and Critical Care MedicineSearch for more papers by this author First published: 30 January 2012 https://doi.org/10.1016/S1754-3207(11)70988-9Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume5, IssueS1September 2011Pages 286-287 RelatedInformation

Objectives To delineate the prevalence of cardiac findings in hypermobile and classic Ehlers-Danlos syndrome and provide longitudinal analysis of aortic root growth.Study design A retrospective chart review was conducted, and data were analyzed for cross-sectional prevalence of aortic dilation and valvular anomalies. The clinical implications of aortic root growth were determined by assessment of progression of aortic root measurements over time and clinical symptoms.Results Patients whose first echocardiogram was obtained in late childhood or adulthood were less likely to have aortic dilation (P <.002) than those whose first echocardiogram was obtained in early childhood. Longitudinally, seven individuals had dilated aortas before age 14, and only one individual continued to show dilation after age 14 (P = .0143). No patient with a normal aortic root in childhood had development of dilation in adulthood. Fifteen of the 252 patients (6.0%) had mitral valve prolapse (MVP), although only one patient (0.4%) had MVP that was mild to moderate.Conclusions Although aortic root size and MVP are increased in patients with these types of Ehlers-Danlos syndrome, they tend to be of little clinical consequence. Echocardiography may still be warranted as part of cardiovascular assessment, but decreased frequency of screening is recommended especially in symptom-free adults. (J Pediatr 2011; 158: 826-30).

BACKGROUND:The sites of action and cellular mechanisms by which spinal cord stimulation reduces neuropathic pain remain unclear.METHODS:We examined the effect of bipolar electrical-conditioning stimulation (50 Hz, 0.2 ms, 5 min) of the dorsal column and lumbar dorsal roots on the response properties of spinal wide dynamic range (WDR) neurons in rats after L5 spinal nerve injury. The conditioning stimulation intensity was set at the lowest current that evoked a peak antidromic sciatic Aα/β-compound action potential without inducing an Aδ- or C-compound action potential.RESULTS:Within 15 min of the dorsal column or root conditioning stimulation, the spontaneous activity rate of WDR neurons was significantly reduced in nerve-injured rats. Conditioning stimulation also significantly attenuated WDR neuronal responses to mechanical stimuli in nerve-injured rats and inhibited the C-component of the neuronal response to graded intracutaneous electrical stimuli applied to the receptive field in nerve-injured and sham-operated rats. It is noteworthy that dorsal column stimulation blocked windup of WDR neuronal response to repetitive intracutaneous electrical stimulation (0.5 Hz) in nerve-injured and sham-operated rats, whereas dorsal root stimulation inhibited windup only in sham-operated rats. Therefore, stimulation of putative spinal substrates at A-fiber intensities with parameters similar to those used by patients with spinal cord stimulators attenuated established WDR neuronal hyperexcitability in the neuropathic condition and counteracted activity-dependent increase in neuronal excitability (i.e., windup).CONCLUSIONS:These results suggest a potential cellular mechanism underlying spinal cord stimulation-induced pain relief. This in vivo model allows the neurophysiologic basis for spinal cord stimulation-induced analgesia to be studied.

Soy consumption is said to prevent or treat atherosclerosis, cancer, pain, and memory deficits, but experimental and clinical evidence to support these claims are lacking. We used in vivo models of inflammation to determine whether a soy diet reduces primary or secondary hyperalgesia. In all three experiments, rats were fed either a soy- or casein-based diet for at least 2weeks before induction of inflammation and for the duration of experiments. Mechanical and heat paw withdrawal thresholds and edema were measured before and several times after induction of inflammation. Primary hyperalgesia was assessed in two models: unilateral intraplantar injection with 0.1ml of 25% complete Freund’s adjuvant (CFA) or 0.1ml of 1% carrageenan. Unilateral injection of the intra-articular knee space with 25% CFA (0.1ml) was used to determine the effects of soy in a model of secondary hyperalgesia. Following intraplantar injection of CFA, soy-fed animals exhibited significantly less paw edema, mechanical allodynia, and heat hyperalgesia compared to casein-fed animals. In the carrageenan model of paw inflammation, soy-fed animals were also less allodynic to mechanical stimuli, than were casein-fed animals, but showed no diet based differences in paw edema or heat hyperalgesia. Soy diet did not affect any of the outcome measures after the intra-articular injection of CFA. Our results suggest that a soy diet significantly decreases aspects of inflammation-induced primary, but not secondary, hyperalgesia in rats.

Background:Acid-sensing ion channels 2 and 3 (ASIC2 and ASIC3, respectively) have been implicated as putative mechanotransducers. Because mechanical hyperalgesia is a prominent consequence of nerve injury, we tested whether male and female ASIC2 or ASIC3 knockout mice have altered responses to mechanical and heat stimuli at baseline and during the 5 weeks after spinal nerve ligation. Methods:Age-matched, adult male and female ASIC2 knockout (n = 21) and wild-type (WT; n = 24) mice or ASIC3 knockout (n = 20) and WT (n = 19) mice were tested for sensitivity to natural stimuli before and after spinal nerve ligation surgery. All animals were first tested for baseline sensitivity to mechanical and heat stimuli and in a novel dynamic mechanical stimulation test. The same testing procedures were then repeated weekly after spinal nerve injury. Results:Compared with their respective WT counterparts, ASIC2 and ASIC3 knockout mice had normal baseline sensitivity to standard mechanical and heat stimuli. However, when exposed to a novel stroking stimulus to test sensitivity to dynamic mechanical stimulation, ASIC3 knockout mice were significantly more sensitive than were WT mice. After spinal nerve ligation, ASIC2 and ASIC3 knockout mice developed mechanical and heat hyperalgesia comparable with that of their respective WT controls. In addition, in both experiments, female mice were more sensitive than male mice to heat at baseline and after the nerve injury. Conclusions:We conclude that ASIC2 and ASIC3 channels are not directly involved in the development or maintenance of neuropathic pain after spinal nerve ligation. However, the ASIC3 channel significantly modulates the sensing of dynamic mechanical stimuli in physiologic condition.

Background Different classes of unmyelinated nerve fibers appear to exhibit distinct conductive properties. We sought a criterion based on conduction properties for distinguishing sympathetic efferents and unmyelinated, primary afferents in peripheral nerves. Methodology/Principal Findings In anesthetized monkey, centrifugal or centripetal recordings were made from single unmyelinated nerve fibers in the peroneal or sural nerve, and electrical stimuli were applied to either the sciatic nerve or the cutaneous nerve endings, respectively. In centrifugal recordings, electrical stimulation at the sympathetic chain and dorsal root was used to determine the fiber's origin. In centrifugal recordings, sympathetic fibers exhibited absolute speeding of conduction to a single pair of electrical stimuli separated by 50 ms; the second action potential was conducted faster (0.61 0.16%) than the first unconditioned action potential. This was never observed in primary afferents. Following 2 Hz stimulation (3 min), activity-dependent slowing of conduction in the sympathetics (8.6 0.5%) was greater than in one afferent group (6.7 0.5%) but substantially less than in a second afferent group (29.4 1.9%). In centripetal recordings, most mechanically-insensitive fibers also exhibited absolute speeding to twin pulse stimulation. The subset that did not show this absolute speeding was responsive to chemical stimuli (histamine, capsaicin) and likely consists of mechanically-insensitive afferents. During repetitive twin pulse stimulation, mechanosensitive afferents developed speeding, and speeding in sympathetic fibers increased. Conclusions/Significance The presence of absolute speeding provides a criterion by which sympathetic efferents can be differentiated from primary afferents. The differences in conduction properties between sympathetics and afferents likely reflect differential expression of voltage-sensitive ion channels.