Psychophysical detection and pain ratings of incremental thermal stimuli: A comparison with nociceptor responses in humans

The capacity of humans to detect and scale the magnitude of pain elicited by small increments in temperature, delivered by a contact thermal stimulator to localized areas of the arm or leg, was measured on non-painful and painful adaption temperatures. Subjects continuously rated the magnitude of any pain sensation elicited by heat increments superimposed on base temperatures of 38, 44, 47 or 48 °C. Detection threshold was also measured using a two-alternative forced choice method. The increment detection thresholds were lower for a continuously painful base of 47 °C than for a non-painful base of 38 °C in normal skin, and likewise were lower for a base of 38 °C following hyperalgesia induced by a mild burn. Incremental pain thresholds were nearly equal to detection thresholds on the base of 47 °C. The sensitivity with which subjects could scale the magnitude of pain was 2–7 times better for increments delivered on a 48 °C as opposed to a 38 °C base.Evoked responses in 6 single C-fiber mechanoheat nociceptive afferents (CMHs) were recorded percutaneously from the peroneal nerves of 3 humans, who were simultaneously judging pain magnitude. For a base of 38 °C, both the pain and the neural response thresholds were an order of magnitude higher than corresponding thresholds on a base of 48 °C. For a base of 47 °C, response thresholds of the CMHs ranged from 0.1 to 0.5 °C and were comparable to detection thresholds of 0.1 to 0.3 °C. The sensitivity with which most nociceptors could signal increment size was 3–4 times better on a 48 °C than a 38 °C base.Incremental pain sensitivity was not altered by a compression block of activity in myelinated afferents that eliminated the sense of cool and touch. Thus, activity in unmyelinated fibers alone could account for the sensitivity to incremental thermal stimuli that were superimposed on a painful base temperature. Further, it is likely that CMH nociceptors alone could provide the peripheral information necessary to detect and to make magnitude judgments of pain elicited by these stimuli.     

Diabetic painful and insensate neuropathy: Pathogenesis and potential treatments

Advanced peripheral diabetic neuropathy (PDN) is associated with elevated vibration and thermal perception thresholds that progress to sensory loss and degeneration of all fiber types in peripheral nerve. A considerable proportion of diabetic patients also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain. One or several manifestations of abnormal sensation and pain are described in all the diabetic rat and mouse models studied so far (i.e., streptozotocin-diabetic rats and mice, type 1 insulinopenic BB/Wor and type 2 hyperinsulinemic diabetic BBZDR/Wor rats, Zucker diabetic fatty rats, and nonobese diabetic, Akita, leptin- and leptin-receptor-deficient, and high-fat diet—fed mice). Such manifestations are 1) thermal hyperalgesia, an equivalent of a clinical phenomenon described in early PDN; 2) thermal hypoalgesia, typically present in advanced PDN; 3) mechanical hyperalgesia, an equivalent of pain on pressure in early PDN; 4) mechanical hypoalgesia, an equivalent to the loss of sensitivity to mechanical noxious stimuli in advanced PDN; 5) tactile allodynia, a painful perception of a light touch; and 5) formalin-induced hyperalgesia. Rats with short-term diabetes develop painful neuropathy, whereas those with longer-term diabetes and diabetic mice typically display manifestations of both painful and insensate neuropathy, or insensate neuropathy only. Animal studies using pharmacological and genetic approaches revealed important roles of increased aldose reductase, protein kinase C, and poly(ADP-ribose) polymerase activities, advanced glycation end-products and their receptors, oxidative-nitrosative stress, growth factor imbalances, and C-peptide deficiency in both painful and insensate neuropathy. This review describes recent achievements in studying the pathogenesis of diabetic neuropathic pain and sensory disorders in diabetic animal models and developing potential pathogenetic treatments.     

Response characteristics of specific thermoreceptive afferents innervating monkey facial skin and their relationship to human thermal sensitivity

The responses of thermoreceptive afferents to steady-state constant skin temperatures and temperature shifts were studied in rhesus monkeys by recording single fiber activity from fine dissected strands of the infraorbital nerve. Eighty-five warm and 134 cold fibers were identified by their specific sensitivity to warming and cooling of their receptive fields, which usually were restricted to single spots less than 1 mm in diameter. Warm fibers increased their firing rates with warming and decreased or ceased firing with cooling, while cold fibers showed an opposite behavior. Mean conduction velocity was 3.4 ± 1.7 m/s in warm fibers, and 9.0 ± 3.4 m/s in cold fibers.In response to constant skin temperatures in the innocuous temperature range below 43°C, warm fibers were active over the range of 30–42°C and showed maximum firing rates at 42°C. On the other hand, cold fibers were responsive to constant temperatures over the range of 20–42°C and their firing frequencies were maximal at 30°C and decreased as steady-state temperatures were raised or lowered. In addition, cold fibers exhibited periodic bursting activity when the temperature was below 35°C. The number of intraburst spikes in each burst increased as the constant temperature was     

Restraint stress suppresses experimental allergic encephalomyelitis in Lewis rats

We studied the effect of restraint stress on experimental allergic encephalomyelitis (EAE), a model for the human disease multiple sclerosis (MS), in Lewis rats. Rats were subjected to 12 h restraint stress for 3 consecutive nights from the first (day 1) or the eighth day (day 8) after sensitization with the antigen (guinea-pig spinal cord). All controlled rats exhibited clinical and histologie signs of EAE. The mean ± SD of incubation time, clinical score (0–4) and histologic score (0–3) for this group were 12.8 ± 1.0 days, 2.7 ± 0.6, and 2.3 ± 0.7, respectively. Restraint stress from day 8 significantly suppressed EAE: the mean ± SD of incubation time, clinical score, and histologic score for this group were 17.2 ± 2.2 days (p < 0.001), 1.8 ± 1.3 (p < 0.05), and 1.5 ± 0.9 (p < 0.02), respectively. Restraint stress from day 1 did not modify EAE. The findings suggest that stressful factors may exert an influence on the clinical course of MS.     

Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model

Cancer pain significantly affects the quality of cancer patients, and current treatments for this pain are limited. C-Jun N-terminal kinase (JNK) has been implicated in tumor growth and neuropathic pain sensitization. We investigated the role of JNK in cancer pain and tumor growth in a skin cancer pain model. Injection of luciferase-transfected B16-Fluc melanoma cells into a hindpaw of mouse induced robust tumor growth, as indicated by increase in paw volume and fluorescence intensity. Pain hypersensitivity in this model developed rapidly (< 5 days) and reached a peak in 2 weeks, and was characterized by mechanical allodynia and heat hyperalgesia. Tumor growth was associated with JNK activation in tumor mass, dorsal root ganglion (DRG), and spinal cord and a peripheral neuropathy, such as loss of nerve fibers in the hindpaw skin and induction of ATF-3 expression in DRG neurons. Repeated systemic injections of D-JNKI-1 (6 mg/kg, i.p.), a selective and cell-permeable peptide inhibitor of JNK, produced an accumulative inhibition of mechanical allodynia and heat hyperalgesia. A bolus spinal injection of D-JNKI-1 also inhibited mechanical allodynia. Further, JNK inhibition suppressed tumor growth in vivo and melanoma cell proliferation in vitro. In contrast, repeated injections of morphine (5 mg/kg), a commonly used analgesic for terminal cancer, produced analgesic tolerance after 1 day and did not inhibit tumor growth. Our data reveal a marked peripheral neuropathy in this skin cancer model and important roles of the JNK pathway in cancer pain development and tumor growth. JNK inhibitors such as D-JNKI-1 may be used to treat cancer pain.     

Antinociceptive effect of matrine on vincristine-induced neuropathic pain model in mice

Chemotherapy drugs treatment causes neuropathic pain, hyperalgesia and allodynia are common components of neuropathic pain, so effectively therapeutic strategy is required. In this study, we evaluated the antinociceptive effects of matrine on vincristine-induced neuropathic pain in mice. Vincristine (100 μg/kg i.p.) was administered once per day for 7 days (day 0–6) in mice. Matrine (15, 30, 60 mg/kg, i.p.) was repeated administration in early phase (day 0–6) or late phase (day 7–13). Hyperalgesia and allodynia were evaluated by withdrawal response using von Frey filaments, plantar and cold-plate on 7, 14 and 21 day. Injection of vincristine produced mechanical hyperalgesia and cold allodynia. Matrine was found to produce a protective role in both von Frey filaments and cold-plate test. The analysis of the effect supports the hypothesis that matrine is useful in therapy of vincristine-induced neuropathic pain. In conclusion, this study demonstrates that administration of matrine is associated with antinociceptive effect on mechanical and cold stimuli in a mice model of vincristine-induced neuropathy pain.     

Thermoresponsiveness of posterior hypothalamic (PH) neurons of rats to scrotal and abdominal thermal stimulation

The thermoresponsiveness of posterior hypothalamic (PH) neurons to localized, incremental thermal heating and cooling between 10–40°C of the abdomen or scrotum was determined in urethane anesthetized, male Sprague–Dawley rats whose core temperature was maintained at 37°C during testing. PH extracellular neuronal activity was recorded along with changes in gastrocnemius muscle EMG activity and temperature (T_ms, indicative of shivering thermogenesis) and intrascapular brown adipose tissue temperature (T_IBATs, indicative of non-shivering thermogenesis). Seventy-five PH neurons were recorded following both scrotal and abdominal trials of thermal stimulation. Nine percent of PH neurons were classified as warm responsive neurons (WRNs), 20% as cold responsive (CRNs), and 71% as temperature nonresponsive neurons (TNRNs), based on their thermal coefficients (TCs). Mean TC for warm PH neurons was significantly increased with scrotal warming between 30–40°C from the mean TC of the same PH WRNs following abdominal warming. Similarly, the thermal coefficient was increased (i.e., was more negative) for cold responsive PH neurons to scrotal cooling (20–10°C) as opposed to the TC of the same PH CRNs for abdominal cooling. No shivering thermogenesis (no change in temperature or EMG activity from gastrocnemius muscle) or non-shivering thermogenesis (no significant increase in IBAT temperatures) occurred with scrotal or abdominal cooling in these 21°C acclimatized rats. The results indicate that a small population of PH neurons are thermoresponsive to localized physiological changes in temperature of the scrotum and abdomen with greater thermoresponsiveness shown of both warm and cold PH neurons to scrotal vs. abdominal thermal stimulation.     

Suppression of C-fibre discharges upon repeated heat stimulation may explain characteristics of concomitant pain sensations

Nociceptors with unmyelinated axons were recorded from the superficial radial nerves of 7 volunteers. A sequence of uniform radiant heat stimuli of 18 s duration, starting from an individually adjusted adapting temperature were used to raise the skin surface temperature by 6°C to a painful level (41–43 °C). These stimuli followed each other at 3 different interstimulus intervals of 35 s, 70 s and 105 s, occurring in a random order. The subjects were asked to track the time course of the stimulus-evoked sensation by manipulating the length of a light bar. Adaptation and stimulus temperatures were chosen to induce sensations of heat and/or pain. All nociceptors studied responded to these stimuli with a phasic response of 3–5 s duration, often followed by a low frequency tonic discharge, lasting as long as the stimulus. No discharges were seen in interstimulus periods. Discharge rates during the phasic responses were linearly related to interval duration, whereas tonic discharges were not influenced by the preceding interval. In parallel readings of pain responses were lower up to the 10th second of the stimulus after short rather than after long intervals. These results indicate that the suppression of C-fibre nociceptor discharges during repetitive stimulation may explain concomitant reductions in the magnitude of human pain sensations.     

Tongue adaptation temperature influences lingual nerve responses to thermal and menthol stimulation

Menthol, a tangible substance present in many orally administered products, can produce a powerful influence on the perceived intensity of subsequent thermal stimulation in humans as well as the response magnitudes of thermally sensitive neurons in rats. However, there are no prior studies examining the influence of adaptation temperature on perceived intensity and/or response magnitudes of thermally sensitive neurons to subsequent menthol stimulation. We identified 32 thermally sensitive neurons that increased their discharge rate to a gradual temperature decrement beginning from 35°C and dropping to 10°C at 1°C. Based on their response threshold, time-to-peak, and range of sensitivity, these thermally sensitive lingual neurons were found to be divisible into two distinct groups. Group 1 neurons (n = 21) responded best to the upper cool range (34–15°C) of the temperature decrement, whereas Group 2 neurons (n = 11) responded to the lower cold range (32–10°C) of the temperature decrement. Our Group 1 and Group 2 neurons may be analogous to low threshold and high threshold cold receptors identified previously in primates. We also examined the responses of lingual neurons to 0%, 25%, 50% and 75% dilution's of a stock menthol concentration (1.28 mM) at 25 and 35°C adaptation temperatures. Menthol responses across all concentrations were far larger after adaptation to 35°C compared to 25°C. Furthermore, only during 35°C adaptation did responses to menthol stimulation persist during the ensuing 20 s after menthol off-set and water on-set. Although an effective coolant, the degree of perceived cooling due to menthol applied to lingual mucosa depends on the temperature of the vehicle and the surface to which it is applied.     

Intrathecal delivery of farnesyl thiosalicylic acid and GW 5074 attenuates hyperalgesia and allodynia in chronic constriction injury-induced neuropathic pain in rats

The role of mitogen-activated protein kinase (MAPK) family has been well defined in neuropathic pain. Ras and c-Raf constitute an important part of MAP kinase family as Ras/Raf/MEK/ERK2 signaling cascade. The present study was designed to investigate the analgesic potential of farnesyl thiosalicylic acid, a novel Ras inhibitor, and GW 5074, a selective c-Raf1 inhibitor, in chronic constriction-induced injury (CCI)-induced peripheral neuropathic pain. Neuropathic pain was induced by placing four loose ligatures around the sciatic nerve. The development of pain was assessed on 14th day in terms of cold allodynia; mechanical hyperalgesia and mechanical allodynia by performing acetone test, pinprick and Von Frey tests, respectively. Farnesyl thiosalicylic acid (2.5, 5 and 10 μg) and GW 5074 (1, 2 and 4 μg) were injected intrathecally on 14th day following nerve ligature to assess their analgesic potential in CCI model. Nerve ligature-induced CCI produced significant neuropathic pain manifestations in terms of cold and mechanical allodynia, and mechanical hyperalgesia. Single intrathecal administration of farnesyl thiosalicylic acid (5 and 10 μg) as well as GW 5074 (2 and 4 μg) significantly attenuated CCI-induced hyperalgesia and allodynia. The analgesic effects of farnesyl thiosalicylic acid and GW 5074 in CCI model suggests that pharmacological inhibition of Ras and c-Raf-1 signaling may be potentially useful for managing neuropathic pain.     

Treatment of painful sensory neuropathy with tiagabine: A pilot study

To evaluate the effect of tiagabine hydrochloride in painful neuropathy in a pilot, open-label study. Painful neuropathy is characterized by preferential involvement of small sensory and autonomic fibers. Tiagabine increases -aminobutyric acid and might enhance the central pain-control mechanisms. Seventeen patients (10 men, 7 women; mean age 51.4±7.7 y) with chronic painful neuropathy (>6 months) were enrolled in this study. Week 0:All pain medications were discontinued. Weeks 1–4: Dose of tiagabine was increased weekly by 4 mg orally up to 16 mg in week 4. Quantitative sensory testing for vibration, cooling, and heat-pain, and quantitative sudomotor axon reflex test (QSART) were done at week 0 and week 4. The McGill Pain Questionnaire was administered weekly.Nine patients completed the study; 8 patients discontinued the treatment. Baseline pain intensity was 6.2±3.1 on the McGill Pain Questionnaire scale (0–10 range). Low doses (4–8 mg) of tiagabine reduced pain symptoms by 16–38%, improving surface pain (37.5%), skin sensitivity (32.8%), burning (38.6%), cold (25.4%) and pain sharpness (29%; p<0.03). Dull and deep pain did not improve. Quantitative sensory testing abnormalities diminished with treatment (p<0.02). Autonomic test results did not change.This pilot study evaluated the potential of tiagabine hydrochloride (Gabitril) in treatment of painful sensory neuropathy. Pain symptoms and quantitative sensory test results improved with treatment, especially at low doses of tiagabine (4–8 mg). Higher doses (12–16 mg) were associated with increased number of adverse events.Tiagabine may have potential benefits for treatment of painful neuropathy; however, assessment of its efficacy in a larger study is needed.This study was sponsored by a grant from Abbott Laboratories and Cephalon, Inc., Westchester, PA, U.S.A.     

Susceptibility of human foetal brain tissue to cool- and freeze-storage

Human second trimester foetal brain tissue was stored for a period of 1–6 weeks under various conditions in an attempt to evaluate factors influencing its susceptibility (cell loss) and survivability. Post-storage viability of mesencephalon, striatum, cerebellum and occipital cortex was assessed by a protocol combining vital staining with cell density counts so that tissue viability and cell loss could be evaluated simultaneously; tissue survivability was evaluated by cell culture. A significant amount of cell loss occurred after 24 h storage at room temperature, after one week at 4°C and by two weeks at −20°C in all structures; storage at −196°C resulted in 17–21% cell loss at the end of a 6 week period. At −20°C the cryoprotective effect of 20% FCS was equivalent to that of 15% FCS + 7% DMSO combined, suggesting potential use of serum in replacement of chemical additives. The procedure for removal of DMSO was critical to cell viability and survivability: single step dilution led to 27–39% greater cell loss than slow, multi-step dilutions. In comparison to fresh, non-stored tissue, immunocytochemical characterization of in vitro propagated stored tissue revealed no changes in the populations of major constituent cell types including neurones, dopaminergic neurones, glial and fibroblast cells. These results provide information on possible conditions under which transplant tissue can be satisfactorily stored depending on the prevailing requirements.     

No adrenergic sensitization of afferent neurons in painful sensory polyneuropathy

Introduction The aim of the present study was to determine (1) if an adrenergic sensitivity of afferent neurons is present in patients with painful polyneuropathy as compared with non–painful polyneuropathy and (2) if there is a correlation between adrenergic sensitisation and the severity of afferent and sympathetic small fiber damage. Methods 10 patients with painful and non painful polyneuropathy and 10 healthy controls were included. The function of small afferent and efferent sympathetic neurons was evaluated. Adrenergic sensitivity of afferent neurons was assessed by cutaneous iontophoresis of norepinephrine. Spontaneous pain, mechanical hyperalgesia as well as warm and heat pain thresholds were measured. Results Iontophoresis of norepinephrine did not induce or enhance spontaneous pain or mechanical allodynia, either in painless or painful polyneuropathies. There was no difference in norepinephrineinduced heat hyperalgesia between both neuropathy groups and healthy controls. The response of afferent neurons to norepinephrine was not correlated with the severity of damage to afferent small fibers or efferent sympathetic vasoconstrictor neurons. Conclusion The results do not support the assumption that in painful polyneuropathies afferent neurons acquire an adrenergic sensitivity after nerve injury and that adrenergic stimulation leads to an exacerbation of spontaneous pain and thermal and mechanical hyperalgesia. This work was supported by the Deutsche Forschungsgemeinschaft (DFG Ba 1921/1–1/2), and the Bundesministerium für Bildung und Forschung (BMBF) Research Network “Neuropathic Pain” and an unrestricted educational grant from Pfizer, Germany.     

Acute cold stress leading to elevated corticosterone neither enhances synaptic efficacy nor impairs LTP in the dentate gyrus of freely moving rats

Exposure to stress has previously been found to impair long-term potentiation (LTP) in the hippocampus. Exposure to stress has also been proposed to induce an LTP-like effect. We examined the effect of acute cold stress on synaptic transmission, neuronal excitability, and LTP induction in the medial perforant path-granule cell synapse of freely moving rats. After obtaining baseline recordings of evoked field potentials at room temperature (23°C), rats were transferred to an environmental cage maintained at 4°C (cold group) or 23°C (control group) and, 90 min later, high-frequency stimulation (HFS) was applied to the medial perforant path. Serum corticosterone measured in trunk blood from rats without implanted electrodes was significantly elevated in cold exposed (28.7 μg/dl) rats relative to control (6.6 μg/dl). Despite increased corticosterone levels indicative of stress activation, cold exposed rats exhibited LTP of the fEPSP slope and population spike of similar magnitude and time course as controls. In addition, there was no stress-specific effect on the fEPSP slope or population spike and no effect on paired-pulse plasticity. Surprisingly, despite extensive cage acclimation, transferring rats to the environmental cage was associated with a reduction in population spike amplitude and an enhancement in paired-pulse facilitation. The results show that acute cold stress leading to elevated serum corticosterone levels neither induces LTP-like increases in synaptic efficacy nor impairs tetanus-evoked LTP in the dentate gyrus of freely moving rats. Thus, impaired working memory during cold stress is not due to an inability of perforant path synapses to express LTP.     

A new animal model of vincristine-induced nociceptive peripheral neuropathy

Using doses close to those used clinically, we have developed an animal model of vincristine-induced nociceptive sensory neuropathy after repeated intravenous injection in male Sprague-Dawley rats. In order to validate the model, three different doses (50, 100 and 150 microg/kg) of vincristine were injected every 2nd day until five injections had been given. The sensory behavioural assessment revealed mechanical hyperalgesia and allodynia associated with cold thermal hyperalgesia and allodynia. With regard to electrophysiological evaluation, we observed a decrease in the nerve conduction velocity in the highest dose group. Morphological studies revealed few degenerated fibers in the sciatic nerve and many degenerated myelinated axons in the fine nerve fibers of the subcutaneous paw tissue. Finally, to develop an animal model, we chose the 150 microg/kg dose because of the good general clinical status of the rats without motor function changes associated with severe sensation disorders like hyperalgesia and allodynia. This model of vincristine-induced painful neuropathy will be used to explore physiopathological mechanisms implied in the genesis of neuropathic pain and also to test new analgesic and neuroprotective drugs.     

Stress exacerbates neuropathic pain via glucocorticoid and NMDA receptor activation

There is growing recognition that psychological stress influences pain. Hormones that comprise the physiological response to stress (e.g., corticosterone; CORT) may interact with effectors of neuropathic pain. To test this hypothesis, mice received a spared nerve injury (SNI) after exposure to 60 min restraint stress. In stressed mice, allodynia was consistently increased. The mechanism(s) underlying the exacerbated pain response involves CORT acting via glucocorticoid receptors (GRs); RU486, a GR antagonist, prevented the stress-induced increase in allodynia whereas exogenous administration of CORT to non-stressed mice reproduced the allodynic response caused by stress. Since nerve injury-induced microglial activation has been implicated in the onset and propagation of neuropathic pain, we evaluated cellular and molecular indices of microglial activation in the context of stress. Activation of dorsal horn microglia was accelerated by stress; however, this effect was transient and was not associated with the onset or maintenance of a pro-inflammatory phenotype. Stress-enhanced allodynia was associated with increased dorsal horn extracellular signal-regulated kinase phosphorylation (pERK). ERK activation could indicate a stress-mediated increase in glutamatergic signaling, therefore mice were treated prior to SNI and stress with memantine, an N-methyl-d-aspartate receptor (NMDAR) antagonist. Memantine prevented stress-induced enhancement of allodynia after SNI. These data suggest that the hormonal responses elicited by stress exacerbate neuropathic pain through enhanced central sensitization. Moreover, drugs that inhibit glucocorticoids (GCs) and/or NMDAR signaling could ameliorate pain syndromes caused by stress.     

Electrophysiological and Behavioral Changes by Phosphodiesterase 4 Inhibitor in a Rat Model of Alcoholic Neuropathy

Objective

Alcoholic neuropathy is characterized by allodynia (a discomfort evoked by normally innocuous stimuli), hyperalgesia (an exaggerated pain in response to painful stimuli) and spontaneous burning pain. The aim of the present study is to investigate the effect of rolipram, a phosphodiesterase 4 inhibitor, against alcohol-induced neuropathy in rats.

Methods

Allodynia was induced by administering 35% v/v ethanol (10 g/kg; oral gavage) to Spraue-Dawley rats for 8 weeks. Rolipram and saline (vehicle) were administered intraperitoneally. Mechanical allodynia was measured by using von Frey filaments. Somatosensory evoked potential (SEP) was proposed as complementary measure to assess the integrity of nerve pathway.

Results

The ethanol-induced mechanical allodynia began to manifest from 3 week, and then peaked within 1 week. Beginning from 3 week, latency significantly started to increased in control group. In rolipram treated rats, the shorter latency was sustained until 8 weeks (p<0.05). The mechanical allodynia, which began to manifest on the 3 weeks, intraperitoneal injections of rolipram sustained statistical difference until 8 weeks, the final week of the study (p<0.05).

Conclusion

This study suggests that rolipram might alleviate mechanical allodynia induced by alcohol in rats, which clearly has clinical implication.     

Influence of low level maternal Pb exposure and prenatal stress on offspring stress challenge responsivity

We previously demonstrated potentiated effects of maternal Pb exposure producing blood Pb(PbB) levels averaging 39 μg/dl combined with prenatal restraint stress (PS) on stress challenge responsivity of female offspring as adults. The present study sought to determine if: (1) such interactions occurred at lower PbBs, (2) exhibited gender specificity, and (3) corticosterone and neurochemical changes contributed to behavioral outcomes. Rat dams were exposed to 0, 50 or 150 ppm Pb acetate drinking water solutions from 2 mos prior to breeding through lactation (pup exposure ended at weaning; mean PbBs of dams at weaning were <1, 11 and 31 μg/dl, respectively); a subset in each Pb group underwent prenatal restraint stress (PS) on gestational days 16–17. The effects of variable intermittent stress challenge (restraint, cold, novelty) on Fixed Interval (FI) schedule controlled behavior and corticosterone were examined in offspring when they were adults. Corticosterone changes were also measured in non-behaviorally tested (NFI) littermates. PS alone was associated with FI rate suppression in females and FI rate enhancement in males; Pb exposure blunted these effects in both genders, particularly following restraint stress. PS alone produced modest corticosterone elevation following restraint stress in adult females, but robust enhancements in males following all challenges. Pb exposure blunted these corticosterone changes in females, but further enhanced levels in males. Pb-associated changes showed linear concentration dependence in females, but non-linearity in males, with stronger or selective changes at 50 ppm. Statistically, FI performance was associated with corticosterone changes in females, but with frontal cortical dopaminergic and serotonergic changes in males. Corticosterone changes differed markedly in FI vs. NFI groups in both genders, demonstrating a critical role for behavioral history and raising caution about extrapolating biochemical markers across such conditions. These findings demonstrate that maternal Pb interacts with prenatal stress to further modify both behavioral and corticosterone responses to stress challenge, thereby suggesting that studies of Pb in isolation from other disease risk factors will not reveal the extent of its adverse effects. These findings also underscore the critical need to extend screening programs for elevated Pb exposure, now restricted to young children, to pregnant, at risk, women.     

Role of glutamate receptors in the dorsal reticular nucleus in formalin‐induced secondary allodynia

The role of glutamate receptors present in the medullary dorsal reticular nucleus (DRt) in the formalin test and formalin‐induced secondary nociception was studied in rats. Secondary mechanical allodynia was assessed with von Frey filaments applied to the rat's hindpaw, and secondary thermal hyperalgesia was evaluated with the tail‐immersion test. The selective glutamate receptor antagonists MK801 (N‐methyl‐d ‐aspartate receptor antagonist), 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) (AMPA/KA receptor antagonist) and A841720 (metabotropic glutamate 1 receptor antagonist) were injected into the DRt before or 6 days after formalin injection in the rat. In the formalin test, the three antagonists significantly reduced the number of flinches in both phases of the test. DRt microinjection of MK801 or A841720, but not of CNQX, reduced both secondary nociceptive behaviors. Moreover, pre‐treatment with the three antagonists injected into the DRt prevented the development of secondary mechanical allodynia and secondary thermal hyperalgesia. Similarly, in these rats, the number of c‐Fos‐like immunoreactive neurons were markedly reduced in both the superficial and deep lamina of the dorsal horn. Our findings support the role of DRt as a pain facilitator in acute and chronic pain states, and suggest a key role of glutamate receptors during the development and maintenance of formalin‐induced secondary allodynia.     

Hyposialorrhea as an early manifestation of Parkinson disease

We sought to determine whether hyposialorrhea is an early manifestation of Parkinson disease (PD). We measured basal and citric acid stimulated secretion of whole saliva in 20 patients with early stage (Hoehn–Yahr I–II) PD who had motor symptoms for less than 1 year and were on no medication and 11 age matched controls. Compared to controls, PD patients had significant reduction of both basal (0.0964 ± 0.08 vs 0.293 ± 0.112 ml/min, p < 0.001) and reflex (0.263 ± 0.213 vs 0.537 ± 0.313 ml/min, p < 0.001) salivary secretion. Our findings confirm that hyposialorrhea is an early autonomic manifestation of PD.