Functional Characterization of At-Level Hypersensitivity in Patients With Spinal Cord Injury.

At-level and above-level hypersensitivity was assessed in patients with chronic complete thoracic spinal cord injury (SCI). Patients were classified using somatosensory mapping (brush, cold, pinprick) and assigned into 2 groups (ie, patients with at-level hypersensitivity [SCIHs, n = 8] and without at-level hypersensitivity [SCINHs, n = 7]). Gender and age-matched healthy subjects served as controls. Quantitative sensory testing (QST), electrically- and histamine-induced pain and itch, laser Doppler imaging, and laser-evoked potentials (LEP) were recorded at-level and above-level in SCI-patients. Six of 8 SCIHs, but 0 of 7 SCINHs patients suffered from neuropathic below-level pain. Clinical sensory mapping revealed spreading of hypersensitivity to more cranial areas (above-level) in 3 SCIHs. Cold pain threshold measures confirmed clinical hypersensitivity at-level in SCIHs. At-level and above-level hypersensitivity to electrical stimulation did not differ significantly between SCIHs and SCINHs. Mechanical allodynia, cold, and pin-prick hypersensitivity did not relate to impaired sensory function (QST), axon reflex flare, or LEPs. Clinically assessed at-level hypersensitivity was linked to below-level neuropathic pain, suggesting neuronal hyperexcitability contributes to the development of neuropathic pain. However, electrically evoked pain was not significantly different between SCI patients. Thus, SCI-induced enhanced excitability of nociceptive processing does not necessarily lead to neuropathic pain. QST and LEP revealed no crucial role of deafferentation for hypersensitivity development after SCI. PERSPECTIVE: At-level hypersensitivity after complete thoracic SCI is associated with neuropathic below-level pain if evoked by clinical sensory stimuli. QST, LEP, and electrically-induced axon reflex flare sizes did not indicate somatosensory deafferentation in SCIHs.

Mechano-insensitive nociceptors are sufficient to induce histamine-induced itch.

The nerve fibres underlying histamine-induced itch have not been fully elucidated. We blocked the lateral femoral cutaneous nerve and mapped the skin area unresponsive to mechanical stimulation, but still sensitive to electrically induced pain. Nerve block induced significantly larger anaesthetic areas to mechanical (100 mN pin-prick, 402 ± 61 cm²; brush, 393 ± 63 cm²) and heat pain stimuli (401 ± 53 cm²) compared with electrical stimulation (352 ± 62 cm², p < 0.05), whereas the anaesthetic area tested with 260 mN (374 ± 57 cm²) did not differ significantly. Histamine was applied by iontophoresis (7.5 mC) at skin sites in which mechanical sensitivity was blocked, but electrical stimulation was still perceived 30 min after the nerve block (n = 9). In these areas iontophoresis of histamine provoked itching in 8/9 subjects with a mean maximum of 4.6 ± 1 (on an 11-point rating scale). Histamine-induced itch can thus be perceived at skin sites where input from mechano-sensitive polymodal nociceptors is blocked. In conclusion, input from mechano-insensitive nociceptors is sufficient to generate histamine-induced itch.

Discriminative sensory characteristics of the lateral femoral cutaneous nerve after mepivacaine-induced block.

Background and objectives Unmyelinated C-fibres comprise the largest group of somatic afferents and have demonstrated a crucial role not only in the perception of high-threshold mechanically, thermally or chemically induced pain, but also in non-harmful low-threshold mechanical stimuli [1,2]. The objective of our study was to characterize differential sensitivity changes of C-fibre related subclasses of high-threshold and low-threshold polymodal nociceptors and low-threshold mechanoreceptors to the local anaesthetic (LA) mepivacaine during nerve block of the purely sensory lateral femoral cutaneous nerve (LFCN) in human. We assumed a diverse response of different classes of afferents to the two different concentrations of the LA mepivacaine (Scandicaine). Methods In a double-blind randomized experimental setting, an ultrasound-guided nerve block of the LFCN was performed in 10 healthy male subjects, each with two different concentrations of mepivacaine (0.5 and 1%). Responsiveness of afferent nerve fibres to different noxious and non-noxious stimuli was tested by Quantitative Sensory Testing (QST) 30, 180, and 300 min after nerve block. Both LA concentrations of mepivacaine were compared for time course of the areas of anaesthesia for the tested sensory modalities. Results Initial extension of anaesthetic areas at 30 min did not differ between both LA concentrations. At 180 min only the anaesthetic areas to nociceptive stimuli were reduced at the site of lower mepivacaine injection (260mN: 204mm2 (18; 244; median difference and 95% confidence interval; p < 0.05), heat: 276mm2 (3; 305)). In contrast, no significant differences were found between the two concentration when non-nociceptive stimuli were used (100mN: 187mm2 (4; 240), p >0.05, brush: 159mm2 (-59; 202)). Conclusion Equal initial sizes of anaesthesia areas for all sensory modalities can be explained by supramaximal perineural LA molecule concentration in both administered mepivacaine dosages. Upon washout of the LA nociceptive function is restored faster as compared to non-nociceptive sensation and higher concentration of the LA are required to maintain the analgesia. Quantitative sensory testing is able to detect different susceptibility of low threshold mechanosensors and subtypes of nociceptive C-fibres to mepivacaine. Using painful mechanical, heat and electrical stimulation different classes of nociceptors will be activated. The analgesic areas to electrical stimulation were particularly small; one might therefore hypothesize that the proposed protocol allows to also differentiate mechano-insensitive ("silent") and mechanosensitive ("polymodal") nociceptors. Implications QST is a non-invasive method to functionally examine sensory modalities and their pharmacological modulation in humans. The method is sufficiently sensitive to differentiate the analgesic properties of mepivacaine at 0.5 and 1% and might also be adequate to different classes of nociceptors. Further development of nociceptive stimuli including supra-threshold encoding characteristics will enable to investigate peripheral analgesic effects more specifically and thus might help to design new analgesics with preferential effect on high frequency discharge of nociceptors.

Treatment-related changes in brain activation in patients with fibromyalgia syndrome.

Little is known about the effects of successful treatment on brain function in chronic pain. This study examined changes in pain-evoked brain activation following behavioral extinction training in fibromyalgia patients. Using functional magnetic resonance imaging, brain activation to painful mechanical stimuli applied to the 2nd phalanx of the left 2nd digit (m. flexor digitorum) was assessed in 10 patients with fibromyalgia syndrome (FM) before and after behavioral extinction training. The behavioral treatment significantly reduced interference from pain in the FM patients. Mechanical pain threshold and pain tolerance increased significantly after treatment. Activation in the insula shifted bilaterally from a more anterior site before treatment to a more posterior location after treatment. The pre- to post-treatment reduction in both interference related to pain and pain severity were significantly associated with bilateral activation in pain-evoked activity in the posterior insula, the ipsilateral caudate nucleus/striatum, the contralateral lenticular nucleus, the left thalamus and the primary somatosensory cortex contralateral to the stimulated side. These data show a relation between successful behavioral treatment and higher activation bilaterally in the posterior insula and in the contralateral primary somatosensory cortex. Future studies should compare responders and non-responders for differential treatment effects and examine in more detail the mechanisms underlying these changes.

NGF enhances electrically induced pain, but not axon reflex sweating.

High-affinity receptors for nerve growth factor (NGF) are found on nociceptors and sympathetic efferents. NGF is known to sensitize nociceptors, increase innervation density, and fire frequency of sympathetic fibers. We explored axonal sensitization of afferent and efferent fibers following intracutaneous injection of NGF in human and pig skin. In humans, frequency-dependent (5, 20, 100 Hz) electrically induced pain was assessed 1, 3, 7, 21, and 49 days post injection. Sweat output was recorded in parallel using the quantitative sudomotor axon reflex test (QSART). Electrically induced pain ratings (7.5 mA for 30 s) significantly increased at the NGF sites for 5 Hz (numeric rating scale [NRS] 6±0.5 vs 3.7±0.4), 20 Hz (NRS 7.2±0.4 vs 5±0.5), and 100 Hz stimulation (NRS 6.9±0.4 vs 5.4±0.3) at day 21, and also for 5 Hz at day 49 (NRS 5.4±0.4 vs 3.8±0.3). Electrically evoked QSART increased frequency dependent, but was not altered by NGF throughout the entire observation period (average QSART at 5 Hz: 3 mL/h/m(2), 20 Hz: 9 mL/h/m(2), 100 Hz: 10 mL/h/m(2)). Similarly, NGF did not change the activity-dependent slowing of conduction of sympathetic efferents (6±2% vs 5.1±1.5%, for 3 minutes, 2 Hz) in pig single-fiber recordings. In parallel to the increased pain ratings recorded in humans, activity-dependent slowing of mechano-insensitive nociceptors was reduced by NGF (18.1±2% vs 29±1.4%). In summary, axonal sensitization of nociceptors by NGF could underlie the hyperalgesia to electrical stimulation. Enhanced responses were limited to nociceptors, as no sensitization was found in sympathetic efferent neurons.

Differential central pain processing following repetitive intramuscular proton/prostaglandin E2 injections in female fibromyalgia patients and healthy controls.

BACKGROUND: While the etiology of fibromyalgia syndrome (FMS) remains unclear, it is assumed that both peripheral and central components are involved. AIMS/METHODS: To investigate central activation patterns following chemically-induced muscle pain we repetitively injected protons (low pH) and prostaglandin E(2) (PGE(2)) in isotonic solution into the left extensor carpi radialis brevis muscle of female FMS patients and female healthy control subjects (HC). The injection of protons/PGE(2) has the advantage that it is not prone to tachyphylaxis compared to capsaicin and hypotonic saline solution. During the repetitive injections continuous pain ratings were recorded and functional magnetic resonance imaging measurements were conducted. RESULTS: Injection of protons/PGE(2) led to activation of the anterior and medial cingulate cortices, contralateral primary sensory cortex, bilateral insula and thalamus, left basal ganglia, left orbitofrontal cortex and the cerebellum in FMS patients. In HC, activations were found only in the anterior, medial, and posterior cingulate cortices, and the primary somatosensory cortex. The contrast between the groups revealed significantly stronger activation for FMS patients in the left anterior insula. Peak pain ratings were comparable between HC and FMS patients, but pain duration (sustained pain) was prolonged in FM. CONCLUSION: Repetitive proton/PGE(2)-induced excitation of muscle tissue led to a more prolonged perception of pain and more wide-spread activation in pain-related brain areas in FMS, especially in the left (ipsilateral) insula, whereas acute protons/PGE(2)-induced pain processing was similar in the two groups. These data provide further evidence for enhanced central pain processing in FMS patients.

Electrically induced quantitative sudomotor axon reflex test in human volunteers.

Chemically-induced quantitative sudomotor axon reflex test (QSART) and quantitative sensory testing (QST) are established clinical tools to assess thin fiber function in humans. We investigated stimulus-response functions to transcutaneous electrical stimuli of different current intensity (3.75 to 10mA) and pulse frequency (5 to 100Hz) comparing sweat output (ml/h/m(2)) and pain intensity (numeric rating scale [NRS], 0-10). Efferent sudomotor and afferent nociceptive responses were recorded after a 30s electrical stimulation period of distal (hand and foot) and proximal (forearm and thorax) body sites with 3 repetitive measures per body site. Sweat responses increased intensity dependently and peaked (~100ml/h/m(2)) at highest currents (10mA) that had been administered. Similarly, pain ratings increased with an escalating current intensity. At a constant stimulus intensity of 7.5mA, sudomotor activity was highest (~75ml/h/m(2)) at a stimulus frequency of 20Hz without further increase at 50 or 100Hz. In contrast, pain ratings increased frequency dependently and reached NRS 7 at 100Hz. Sudomotor activity, but not pain ratings, was significantly different between the body sites (p<0.05, ANOVA) with maximum sweat responses obtained at the ventral forearm. Varying response patterns for higher stimulation frequencies between sweating (peak maximum at 20Hz) and pain (maximum at 100Hz) might indicate differential axonal properties of sympathetic efferent and nociceptive afferent fibers. Electrically induced QSART could be a useful explorative and clinical method to indirectly study characteristics of frequency-dependent axonal excitability changes of sudomotor fibers.

Nerve growth factor-evoked nociceptor sensitization in pig skin in vivo.

Peripheral sensitization of skin nociceptors by nerve growth factor (NGF) was explored in pig skin in vivo. As an objective output measure, the area of axon-reflex-mediated erythema was assessed upon mechanical, thermal, chemical, and electrical stimuli delivered at 1, 3, and 7 days after i.d. injection of 1 microg NGF into the pig's back skin (n = 8). Pretreatment with NGF provoked a sensitization to mechanical (600 mN), thermal (10 sec 49 degrees C) and chemical (15 microl, pH 3) stimuli that lasted for 7 days. No sensitization, however, was found in response to weak mechanical (100 mN), weak thermal (10 sec 45 degrees C), or electrical stimuli. Irrespective of the skin pretreatment (NGF or PBS vehicle control), the area of electrically induced erythema decreased upon repetition (days 1-7) by 70% (P < 0.05). Sensitization of sensory endings by NGF upon mechanical, heat, and chemical stimuli suggests recruitment of sensory transducer molecules [e.g., TRPV1, acid-sensing ion channels (ASICs)]. In contrast, the gradual decrease in electrically induced erythema over 7 days might be attributable to axonal desensitization and possibly activity-dependent down-regulation of sodium channels. Thus, long-lasting sensitization processes of nociceptor endings or axonal sodium channel desensitization mechanisms can be explored in the pig as a translational experimental animal model.

NGF induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin.

Nerve growth factor (NGF) modulates sensitivity and sprouting of nociceptors. We explored the spatial and temporal sensitization induced by NGF injection (1 microg) in human skin. Hyperalgesia was investigated in 16 volunteers (36+/-9 years) at day 1, 3, 7, 21, and 49. Areas of mechanical (brush, pin-prick) and heat (43 degrees C) sensitization were mapped and thermal (heat and cold) pain thresholds, mechanical (impact stimulation) and electrically evoked pain, and axon reflex flare were assessed. No spontaneous pain or local inflammation was recorded upon NGF injection and during 49 days. Sensitization to heat was maximum at day 3 and lasted 21 days. Hyperalgesia to cold was recorded at day 7 and 21. Hypersensitivity to mechanical impact stimuli developed delayed, reached maximum at day 21, and persisted throughout 49 days. Fifty percent of all volunteers reported a static allodynia to tonic pressure until day 21. Electrical stimulation at 7.5 mA was more painful at the NGF site at day 21, which correlated significantly to maximum impact pain. Axon reflex flare was unaffected by NGF. Sensitization was limited to the NGF injection site, no touch- or pin-prick evoked secondary hyperalgesia was observed. Spatially restricted hyperalgesia indicates a peripheral rather than central mechanism. The temporal profile of lasting nociceptor sensitization suggests an altered peripheral axonal expression of sensory proteins specifically leading to mechanical and thermal sensitization. Intradermal NGF administration provokes a pattern of sensitization that can be used as experimental model for neuropathic pain.

Long-acting local anesthetics attenuate FMLP-induced acute lung injury in rats.

BACKGROUND: Endothelin-1 (ET-1) is a mediator of lung diseases and a potent pulmonary vasoconstrictor. In addition to thromboxane A2, it participates in the formation of lung edema. Both lidocaine and mepivacaine attenuate the increase of pulmonary arterial pressure (PAP) and lung edema development. We examined the effects of procaine, bupivacaine, and ropivacaine on experimentally evoked PAP increase and ET-1 release. METHODS: PAP and lung weight were measured in isolated rat lungs during perfusion with Krebs-Henseleit hydroxyethyl starch buffer. Bupivacaine, ropivacaine, or procaine was added to the solution at concentrations of 10(-2)-10(-7) mg/kg. ET-1 levels were measured in the perfusate by enzyme-immunoassay, and thromboxane A2 levels were assayed by radioimmunoassay. N-formyl-L-leucine-methionyl-L-phenylalanine was used to activate human polymorphonuclear neutrophils. RESULTS: Bupivacaine, ropivacaine, and procaine significantly attenuated increases of PAP (P < 0.05) and resulted in a reduction of lung weight in these treatment groups compared with the sham group (P < 0.05). The long-acting anesthetics bupivacaine and ropivacaine (P < 0.05), but not procaine, reduced ET-1 levels, produced low inflammation rates, and did not affect lung structures at doses from 10(-3) to 10(-6) mg/kg. CONCLUSION: Bupivacaine and ropivacaine attenuated N-formyl-L-leucine-methionyl-L-phenylalanine-induced PAP, reduced lung edema, and diminished ET-1 release. Lidocaine and mepivacaine are more effective in reducing PAP and edema formation, but long-acting local anesthetics also inhibit ET-1 depletion and therefore have increased anti-inflammatory properties.

Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans.

BACKGROUND AND OBJECTIVES: The most abundant malignant brain tumor in human is glioblastoma and patients with this type of tumor have a poor prognosis with high mortality. Glioblastoma are characterized particularly by fast growth and a dependence on blood vessel formation for survival. Cannabinoids (CBs) inhibit tumor growth by inducing apoptosis of tumor cells and impairing tumor angiogenesis. The distribution of CB1 and CB2 receptors in glioblastoma and associated endothelial vessels is still unknown. METHODS: Tissue samples were collected consecutively after neurosurgery of 19 patients suspected glioblastoma and examined immunohistochemically for CB1 and CB2 receptor expression. Vessel endothelial cells of the sections were immunocytochemically identified by using a primary antibody against PECAM-1. Double labelling was performed for CB receptors and endothelial cells of the vessels by DAPI staining. RESULTS: In endothelia of control tissue, about 24% and 45% of the cells were positive for CB1 and CB2 receptors. In glioblastoma endothelial cells, CB1 and CB2 receptors were present in about 38% and 54% of the cells respectively. In comparison to CB1, an elevated CB2 receptor expression was identified in glioblastoma. CONCLUSIONS: The abundant expression and distribution of CB2 receptors in glioblastoma and particularly endothelial cells of glioblastoma indicate that impaired tumor growth in presence of CB may be associated with CB2 activation. Selective CB2 agonists might become important targets attenuating vascular endothelial growth factor (VEGF) signalling and thereby diminishing neoangiogenesis and glioblastoma growth.

Tetrahydrocannabinol (Delta 9-THC) Treatment in Chronic Central Neuropathic Pain and Fibromyalgia Patients: Results of a Multicenter Survey.

Central neuropathic pain is difficult to treat, but delta 9-Tetrahydrocannabinol (delta 9-THC) may be a promising therapeutic agent. We administered in 172 patients on average 7.5 mg delta 9-THC over 7 months. Of these, 48 patients prematurely withdrew due to side effects, insufficient analgesia, or expense of therapy. Thus, 124 patients were assessed retrospectively in a multicenter telephone survey. Reported changes in pain intensity, recorded on a numeric rating scale (NRS), Pain Disability Index (PDI), Medical Outcomes Short-Form (SF-12), Quality of Life Impairment by Pain (QLIP), Hospital Anxiety Depression Scale (HADS), and amount of concomitant pain medication were recorded. Psychometric parameters (PDI, SF-12, QLIP, HADS) and pain intensity improved significantly during delta 9-THC treatment. Opioid doses were reduced and patients perceived THC therapy as effective with tolerable side effects. About 25% of the patients, however, did not tolerate the treatment. Therapy success and tolerance can be assessed by a transient delta 9-THC titration and its maintained administration for several weeks. The present survey demonstrates its ameliorating potential for the treatment of chronic pain in central neuropathy and fibromyalgia. A supplemental delta 9-THC treatment as part of a broader pain management plan therefore may represent a promising coanalgesic therapeutic option.

Painful and nonpainful phantom and stump sensations in acute traumatic amputees.

BACKGROUND: The formation, prevalence, intensity, course, and predisposing factors of phantom limb pain were investigated to determine possible mechanisms of the origin of phantom limb pain in traumatic upper limb amputees. METHODS: Ninety-six upper limb amputees participated in the study. A questionnaire assessed the following question: side, date, extension, and cause of amputation; preamputation pain; and presence or absence of phantom pain, phantom and stump sensations or stump pain or both. RESULTS: The response rate was 84%. Sixty-five (81%) participants returned the questionnaire. In 64 (98.5%) participants a traumatic injury led to amputation; the amputation was necessary because of infection in one patient (1.5%). The median follow-up time (from amputation to evaluation) was 3.2 years (range, 0.9-3.8 years) The prevalence of phantom pain was 44.6%, phantom sensation 53.8%, stump pain 61.5%, and stump sensation 78.5%. After its first appearance, phantom pain had a decreasing course in 14 (48.2%) of 29 amputees, was stable in 11 (37.9%) amputees, and worsened in 2 (6.9%) of 29 amputees. Stump pain had a decreasing course in 19 (47.5%) of 40 amputees but was stable in 12 (30%) amputees. Phantom pain occurred immediately after amputation in 8 (28%) of 29 amputees between 1 month and 12 months in 3 (10%) amputees and after 12 or more months in 12 (41%) amputees. CONCLUSION: Stump pain and stump sensation predominate traumatic amputees' somatosensory experience immediately after amputation; phantom pain and phantom sensations are often long-term consequences of amputation. Amputees experience phantom sensations and phantom pain within 1 month after amputation, a second peak occurs 12 months after amputation. Revised diagnostic criteria for phantom pain are proposed on the basis of these data.

Nociceptor sensitization to mechanical and thermal stimuli in pig skin in vivo.

Primary hyperalgesia to mechanical and thermal stimuli are major clinical symptoms of inflammatory pain and can be induced experimentally by ultraviolet-B (UV-B) irradiation in humans. We set-up a pig model in order to have more options for pharmacological intervention on primary hyperalgesia. Pig skin was irradiated with a dose one- to threefold higher than the minimum erythema dose (MED) and investigated for mechanical and heat responsiveness 24 and 48 h post UV-B treatment. C-fiber activation upon mechanical and thermal stimulation was assessed indirectly by extent of the axon reflex erythema (flare) measured by laser Doppler imaging. Mechanical stimulation with von Frey filaments (100 mN) induced flare responses in UV-B treated skin at 24 and 48 h, but no effect was measured in normal untreated skin. Increased mechanical stimulation (600 mN) elicited a small flare response in normal skin in an area of 1.8 cm(2) on average that was extending about 2.5 cm(2) in the UV-B irradiated sites. Thermal stimuli provoked in normal pig skin flare areas of approximately 2 cm(2) (45 degrees C, 10 s) and 4.5 cm(2) (47 degrees C, 10 s) which increased to about 3.5 cm(2) (45 degrees C) and 5.5 cm(2) (47 degrees C) following UV-B irradiation at 24 and 48 h. No significant differences of mechanically or thermally induced hypersensitivity were seen between 24 and 48 h after irradiation. We conclude that UV-B induced mechanical and heat sensitization of primary afferent nociceptors can be assessed in pig skin, providing a new human-like model of primary hyperalgesia. Sensitization of primarily mechano-insensitive (silent) nociceptors, which are underlying the flare response in humans, most probably contributes to the observation presented here.

Rapid flare development evoked by current frequency-dependent stimulation analyzed by full-field laser perfusion imaging.

We analyzed, with a new imaging technique, the rapid axon reflex flare responses in human skin upon transcutaneous delivery of electrical stimuli at 1, 5, 10 and 50 Hz in single bursts of five pulses each. Two-dimensional perfusion images covering an area of 8 x 8 cm(2) were captured at 25 Hz and their averages saved at 0.5 Hz. The stimulation caused an axon reflex flare (maximum 3 cm(2), 20 s after stimulation) that gradually resolved within 2 min. Maximum flare responses developed at 5 Hz, whereas pain ratings increased with stimulation frequency. The highest neuropeptide release at 5 Hz correlates to the discharge characteristics of mechanoinsensitive C-fibers, whereas the maximum pain intensity at 50 Hz may be attributed to the activation of A-delta fibers.

Potentiation of nociceptive responses to low pH injections in humans by prostaglandin E2.

UNLABELLED: Inflammation and trauma lead to tissue acidification and release of inflammatory mediators, including prostaglandin E2 (PGE2). Protons can evoke pain through acid-sensing ion channels (ASICs) and TRPV1 receptors. In this study, we examined whether PGE2 can potentiate proton-induced nociception in humans on injection into skin and muscle. Psychophysical and vascular responses to microinjections of protons (pH 6.0 and 6.5), PGE2 (10-6 and 10-7 M) and their combinations into forearm skin (30 microL) or anterior tibial muscle (50 microL) were assessed in 16 male subjects. Pain intensity, axon reflex erythema, and heat pain thresholds were recorded after skin challenge; pain intensity and thresholds for pressure-evoked pain were recorded after intramuscular injections. Intradermal or intramuscular injections of PGE2 induced very low levels of pain similar to saline. Administration of low pH caused moderate pain within 5 seconds that declined rapidly over 15 to 20 seconds. In comparison, coinjection of low pH with PGE2 led to a biphasic profile of the pain response. Combined pH + PGE2 stimulation provoked significantly increased pain in the second phase after injections (20 to 100 seconds) both in skin and muscle, whereas the initial injection pain was not enhanced. Heat pain thresholds were reduced after PGE2 and combined pH + PGE2, whereas flare responses were rather attenuated on coadministration of low pH with PGE2. Intriguingly, when compared with skin, muscle pain was significantly lower in the initial phase (0 to 15 seconds) but significantly higher in the second phase (20 to 100 seconds after injection). PERSPECTIVE: PGE2 can potentiate nociceptor activation by protons in human skin and muscle, indicated by increased sustained pain ratings. This can be best explained by TRPV1 sensitization in the presence of PGE2, a mechanism potentially relevant for inflammatory and injury-induced pain.

Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief.

OBJECTIVE: Fibromyalgia (FM) is a chronic pain syndrome characterized by a distinct mechanical hyperalgesia and chronic pain. Recently, cannabinoids have been demonstrated as providing anti-nociceptive and anti-hyperalgesic effects in animal and human studies. Here, we explored in nine FM patients the efficacy of orally administered delta-9-tetrahydrocannabinol (THC) on electrically induced pain, axon reflex flare, and psychometric variables. RESEARCH DESIGN AND METHODS: Patients received a daily dose of 2.5-15 mg of delta-9-THC, with a weekly increase of 2.5 mg, as long as no side effects were reported. Psychometric variables were assessed each week by means of the West Haven-Yale Multidimensional Pain Inventory (MPI), Pittsburgh Sleep Quality Index (PSQI), Medical outcome survey-short form (MOS SF-36), the Pain Disability Index (PDI), and the Fibromyalgia Impact Questionnaire (FIQ). In addition, patients recorded daily, in a diary, their overall pain intensity on a numeric scale. Each week, pain and axon reflex flare was evoked experimentally by administration of high intensity constant current pulses (1 Hz, pulse width 0.2 ms, current increase stepwise from 2.5-12.5 mA every 3 minutes) delivered via small surface electrodes, attached to the volar forearm skin. MAIN OUTCOME MEASURES: Daily pain recordings by the patient, experimentally induced pain, and axon reflex flare recorded by a laser Doppler scanner. RESULTS: Five of nine FM patients withdrew during the study due to adverse side effects. Delta-9-THC had no effect on the axon reflex flare, whereas electrically induced pain was significantly attenuated after doses of 10-15 mg delta-9-THC (p < 0.05). Daily-recorded pain of the FM patients was significantly reduced (p < 0.01). CONCLUSIONS: This pilot study demonstrated that a generalized statement that delta-9-THC is an analgetic drug cannot be made. However, a sub-population of FM patients reported significant benefit from the delta-9-THC monotherapy. The unaffected electrically induced axon reflex flare, but decreased pain perception, suggests a central mode of action of the cannabinoid.

Reduction of pulmonary edema by short-acting local anesthetics.

BACKGROUND AND OBJECTIVES: Local anesthetics (LAs) possess a variety of effects that cannot be explained by the typical block of neuronal sodium channels. Antithrombotic effects of LAs are well known, but LAs also act as bactericides. Therefore, an investigation of the influence of LAs on the inflammatory response of the isolated rat lung (n = 78) to an N-formyl-l-leucin-methionyl-l-phenylalanine (FMLP) stimulus was performed. METHODS: The experiments were performed on isolated and ventilated rat lungs perfused with cell-free and plasma-free buffer. LAs (lidocaine and mepivacaine) were injected in various concentrations before application and activation of human granulocytes by FMLP. Pulmonary arterial pressure (PAP) and lung weight gain were monitored continuously. LAs in final dosages from 10(-2) to 10(-7) mg/kg body weight (n = 6 each) were injected into the pulmonary artery before treatment with FMLP (10(-6) M) to induce pulmonary arterial hypertension. Perfusate samples were taken intermittently to determine thromboxane A(2) (TX A(2)) and endothelin-1 concentrations. Microscopic analyses were performed to assess the degree of lung injury. RESULTS: Pretreatment with LAs significantly reduced the FMLP-induced PAP increase (treatment group v sham group: 0.5 to 5 mm Hg v 8 mm Hg; P < .05) and the release of endothelin-1 (2.4 v 5 fmol/mL). Histologic damage seen as acute granulocytic alveolitis was reduced by lidocaine and mepivacaine, even below clinically relevant concentrations. CONCLUSION: LA pretreatment reduces inflammatory reactions after FMLP stimulus.

Duration of effects of aspirin on platelet function in healthy volunteers: an analysis using the PFA-100.

STUDY OBJECTIVE: The aim of the study was to determine the duration and effects of aspirin on platelet function. STUDY DESIGN: Prospective investigation. SETTING: Blood samples from volunteers. PATIENTS AND MONITORING: Ten healthy male volunteers took part in this investigation. After having measured baseline hemostatic parameters, 2000-mg aspirin was taken orally. Subsequently, the hemostatic profile had been compiled daily for a duration of 4 days after ingestion. MEASUREMENTS AND MAIN RESULTS: Platelet function was analyzed (1) after 3 hours and (2) daily for 4 days by the platelet function analyzer (PFA-100, Dade Co, Miami, Fla), which represents a sensitive investigation method for measuring platelet function and dysfunction. Routine hemostatic parameters were investigated. Three hours after ingestion of aspirin, abnormal PFA-100 values could be detected. Further detectable elevated values were found during the following 3 days. CONCLUSION: Effects of single-dose aspirin 2000 mg on platelet function were detected after 3 hours and had been lasting for the following 3 days. This result shows that PFA-100 may help by evaluating hemostasis during the preoperative period.