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Zsuzsanna Wiesenfeld-Hallin

Publications and source records attributed to Zsuzsanna Wiesenfeld-Hallin.

At least 19 recordsLinked to original sources
PubMed2006

Lacosamide, a new anti-epileptic, alleviates neuropathic pain-like behaviors in rat models of spinal cord or trigeminal nerve injury.

The effect of systemic administration of lacosamide, a newly developed anti-epileptic, on neuropathic pain-like behaviors was examined in rats after ischemic injury to the infraorbital nerve or spinal cord using a photochemical method. In rats with infraorbital nerve injury, lacosamide reduced mechanical hypersensitivity and the effect was markedly stronger in female than in male rats. In spinal cord injured female rats 10-20 mg/kg lacosamide dose-dependently alleviated the mechanical and cold allodynia-like behaviors without causing motor impairments or marked sedation. Administration of lacosamide twice daily at 20 mg/kg for 7 days totally alleviated the allodynia-like state in spinally-injured rats with no tolerance. Following treatment cessation the cold and the static allodynia reappeared but the effect on dynamic mechanical allodynia (brushing) was maintained until day 11. Lacosamide also produced hypothermia at antinociceptive doses in rats. It is suggested that this novel compound may be useful as an analgesic for treating central and trigeminal neuropathic pain. Furthermore, there may be a gender difference to the effect of lacosamide with female rats being more responsive to the treatments.

Acetamides↗
PubMed2006

Effect of acute and chronic administration of caffeine on pain-like behaviors in rats with partial sciatic nerve injury.

Caffeine, used in many pain medications as an adjuvant analgesic, is an adenosine A1 and A2A receptor antagonist. Here we examined the effects of acute or chronic caffeine administration in rats after partial sciatic nerve injury. The hindpaw response to mechanical or cold stimulation was assessed following photochemically induced sciatic nerve injury which leads to hypersensitivity to these stimuli. Caffeine was administered i.p. acutely or in the drinking water chronically. The mechanical and cold hypersensitivity of sciatic nerve-injured rats was dose-dependently alleviated by acute systemic administration of caffeine (10-80 mg/kg). The effect of caffeine was, however, associated with side effects including locomotor stimulation or depression. Chronic oral administration (average daily doses 27.5 mg/kg/day or 61.5 mg/kg/day for 2 weeks) of caffeine starting at the time of nerve injury did not significantly affect the development of pain-like behaviors. Thus, acute, but not long term, caffeine intake reduced neuropathic pain state in nerve-injured rats, but only at very high doses. The potential hyperalgesic effect of chronic A1 adenosine receptor blockade may have been compensated for by an antinociceptive effect of caffeine through antagonism of A2A receptors and tolerance development.

Animals↗
PubMed2006

Phenotyping of sensory and sympathetic ganglion neurons of a galanin-overexpressing mouse--possible implications for pain processing.

The distribution of galanin was studied in the lumbar 5 dorsal root ganglia (DRGs) and spinal cord, superior cervical ganglia (SCGs), and skin of transgenic mice overexpressing galanin under the dopamine beta-hydroxylase (DBH) promoter (GalOE-DBH mice) and in wild type (WT) mice. The DRGs and spinal cord were analysed before and after a unilateral, complete transection (axotomy) of the sciatic nerve and after dorsal rhizotomy. Both galanin protein and transcript were studied by, respectively, immunohistochemistry and in situ hybridization. Increased galanin expression was observed in several small, medium-sized and large DRG neuron profiles (NPs) in the naïve transgenic mouse, frequently in neurons lacking calcitonin gene-related peptide (CGRP) and isolectin B4-binding. This lack of coexistence was particularly evident in the medium-sized/large NPs. In the dorsal horn of the spinal cord, no differences were detected between GalOE-DBH and WT mice, both displaying a strong galanin-positive neuropil in the superficial laminae of the dorsal horn, but the transgenic mice showed a more abundant galanin-positive innervation of the ventral horn. A 12-day dorsal rhizotomy, surprisingly, failed to alter the galanin staining patterns in the dorsal (and ventral) dorsal horn. Unilateral axotomy induced upregulation of galanin in DRG NPs of all sizes in both types of mouse. In the hindpaw skin, a profuse galanin-positive fiber plexus was observed in sweat glands and around blood vessels of the transgenic mice, being much more restricted in WT mice. Finally, GalOE mice exhibited a strong galanin-like immunoreactivity in most SCG NPs. The overexpression of the peptide in DRGs and SCGs was paralleled by increased mRNA levels. The present results show that overexpression of galanin under the control of the DBH promoter does not only occur, as expected in these mice, in noradrenline/adrenaline neurons but also in DRG neurons, particularly in large and medium-sized NPs. To what extent and how this overexpression pattern is related to the previously shown elevated pain threshold under normal and lesion conditions is discussed [Grass, S., Crawley, J.N., Xu, X.J., Wiesenfeld-Hallin, Z., 2003a. Reduced spinal cord sensitization to C-fibre stimulation in mice over-expressing galanin. Eur. J. Neurosci. 17, 1829-1832; Hygge-Blakeman, K., Brumovsky, P., Hao, J.X., Xu, X.J., Hökfelt, T., Crawley, J.N., Wiesenfeld-Hallin, Z., 2004. Galanin over-expression decreases the development of neuropathic pain-like behaviour in mice after partial sciatic nerve injury. Brain Res. 1025, 152-158].

Animals↗
PubMed2005

Behavioral changes and trigeminal ganglion sodium channel regulation in an orofacial neuropathic pain model.

We used a photochemical method to generate a partial ischemic injury to the infraorbital branch of the trigeminal nerve in rats. Following injury, rats developed a bilateral persistent hypersensitivity to mechanical stimulation in the territory innervated by the infraorbital nerve. In addition, spread of mechanical hypersensitivity beyond the facial region was noted. Heat hypersensitivity was also present, although to a lesser extent and of a shorter duration. In some rats, excessive facial grooming/scratching were observed. Morphological examination revealed a graded damage to the irradiated portion of the infraorbital nerve that was related to the duration of laser irradiation. Investigations of gene expression changes in injured trigeminal ganglion neurons of animals with behavioral signs of neuropathic pain demonstrated that the sodium channel alpha-subunit Na(v)1.3-absent in sham-operated animals-was expressed to a limited extent. mRNAs for Na(v)1.8 and Na(v)1.9 were reduced both with respect to proportions of expressing neurons and to intensities, whereas the beta 3 subunit was markedly upregulated. mRNA levels of p11, a regulatory factor that facilitates the surface expression of Na(v)1.8, were unchanged. Previous findings have shown that injury to the trigeminal nerve branches may elicit responses that differ from those of segmental spinal nerves. Despite this we conclude that the key sodium channel regulations that are reported as consequences of nerve damage in the dorsal root ganglia seem to appear also in the trigeminal ganglion. Thus, novel analgesic drugs designed to target the sodium channel subtypes involved could be of use for the treatment of orofacial pain.

Adaptation, Physiological↗
PubMed2005

Galanin and spinal nociceptive mechanisms: recent results from transgenic and knock-out models.

Genetically modified mice with transgenic overexpression of galanin or depletion of genes for galanin or galanin receptors have become available, providing a new approach for analyzing the role of galanin in nociception. Mice overexpressing galanin had a moderate heat hypoalgesia, reduced spinal sensitization after repetitive C-fiber stimulation and reduced development of neuropathic pain-like behavior after sciatic nerve injury. On the other hand, mice lacking the GALR1 receptor (Galr1-/-) exhibited only slight increase in heat nociception in the hot plate, but not tail flick, test and showed no increase in spinal sensitization. The duration, but not magnitude, of neuropathic pain-like behaviors, was increased in Galr1-/- mice after nerve injury. These results support an inhibitory effect of galanin on nociception, but the physiological role played by galanin via GALR1 receptors needs to be further studied.

Animals↗
PubMed2005

Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome.

Several studies have reported functional improvement after transplantation of neural stem cells into injured spinal cord. We now provide evidence that grafting of adult neural stem cells into a rat thoracic spinal cord weight-drop injury improves motor recovery but also causes aberrant axonal sprouting associated with allodynia-like hypersensitivity of forepaws. Transduction of neural stem cells with neurogenin-2 before transplantation suppressed astrocytic differentiation of engrafted cells and prevented graft-induced sprouting and allodynia. Transduction with neurogenin-2 also improved the positive effects of engrafted stem cells, including increased amounts of myelin in the injured area, recovery of hindlimb locomotor function and hindlimb sensory responses, as determined by functional magnetic resonance imaging. These findings show that stem cell transplantation into injured spinal cord can cause severe side effects and call for caution in the consideration of clinical trials.

Analysis of Variance↗
PubMed2005

Increased nociceptive response in mice lacking the adenosine A1 receptor.

The role of the adenosine A1 receptor in nociception was assessed using mice lacking the A1 receptor (A1R-/-) and in rats. Under normal conditions, the A1R-/- mice exhibited moderate heat hyperalgesia in comparison to the wild-type mice (A1R+/+). The mechanical and cold sensitivity were unchanged. The antinociceptive effect of morphine given intrathecally (i.t.), but not systemically, was reduced in A1R-/- mice and this reduction in the spinal effect of morphine was not associated with a decrease in binding of the mu-opioid ligand DAMGO in the spinal cord. A1R-/- mice also exhibited hypersensitivity to heat, but not mechanical stimuli, after localized inflammation induced by carrageenan. In mice with photochemically induced partial sciatic nerve injury, the neuropathic pain-like behavioral response to heat or cold stimulation were significantly increased in the A1R-/-mice. Peripheral nerve injury did not change the level of adenosine A1 receptor in the dorsal spinal cord in rats and i.t. administration of R-PIA effectively alleviated pain-like behaviors after partial nerve injury in rats and in C57/BL/6 mice. Taken together, these data suggest that the adenosine A1 receptor plays a physiological role in inhibiting nociceptive input at the spinal level in mice. The C-fiber input mediating noxious heat is inhibited more than other inputs. A1 receptors also contribute to the antinociceptive effect of spinal morphine. Selective A1 receptor agonists may be tested clinically as analgesics, particularly under conditions of neuropathic pain.

Adenosine A1 Receptor Agonists↗
PubMed2005

Sex differences in pain perception.

BACKGROUND: A number of studies have demonstrated a higher prevalence of chronic pain states and greater pain sensitivity among women compared with men. Pain sensitivity is thought to be mediated by sociocultural, psychological, and biological factors. OBJECTIVE: This article reviews laboratory studies that provide evidence of sex differences in pain sensitivity and the response to analgesic drugs in animals and humans. The biological basis of such differences is emphasized. METHODS: The literature from this relatively new field was surveyed, and studies that clearly illustrate the differences in pain mechanisms between the sexes are presented. Using the search terms sex, gender, and pain, a review was conducted of English-language literature published on MEDLINE between January 1980 and August 2004. RESULTS: Although differences in pain sensitivity between women and men are partly attributable to social conditioning and to psychosocial factors, many laboratory studies of humans have described sex differences in sensitivity to noxious stimuli, suggesting that biological mechanisms underlie such differences. In addition, sex hormones influence pain sensitivity; pain threshold and pain tolerance in women vary with the stage of the menstrual cycle. Imaging studies of the brain have shown differences between men and women in the spatial pattern and intensity of response to acute pain. Among rodents, females are more sensitive than males to noxious stimuli and have lower levels of stress-induced analgesia. Male rodents generally have stronger analgesic response to mu-opioid receptor agonists than females. Research on transgenic mice suggests that normal males have a higher level of activity in the endogenous analgesic system compared with normal females, and a human study has found that mu-receptors in the healthy female brain are activated differently from those in the healthy male brain. The response to kappa-opioids, which is mediated by the melanocortin-1 receptor gene in both mice and humans, is also different for each sex. CONCLUSION: Continued research at the genetic and receptor levels may support the need to develop gender-specific drug therapies.

Analgesics↗
PubMed2004

Galanin over-expression decreases the development of neuropathic pain-like behaviors in mice after partial sciatic nerve injury.

The neuropeptide galanin may have a role in modulation of nociception, particularly after peripheral nerve injury. Here we assessed the development of neuropathic pain-like behaviors in mice overexpressing galanin under the dopamine beta-hydroxylase promoter. Unoperated galanin over-expressing mice exhibited a moderately reduced sensitivity to noxious heat. Both galanin over-expressing mice and wild-type controls developed mechanical and heat hypersensitivity after photochemically induced partial sciatic nerve ischemic injury. The magnitude and persistence of such pain-like behaviors were significantly less, and recovery was faster in galanin over-expressing mice compared to wild types. However, the recovery from toe-spread deficits did not differ between galanin over-expressing and wild-type mice after a crush injury to the sciatic nerve. Thus, early recovery in pain-like response is unlikely to result from accelerated regeneration in the galanin over-expressing mice. Immunohistochemical analysis showed that galanin is over-expressed both in small and large dorsal root ganglion cells in the transgene mouse, whereas large galanin-positive neurons were never seen in wild-type mice. The present results in general support an inhibitory role of galanin in nociception and indicate that increased availability of galanin in spinal dorsal horn at the time or shortly after nerve injury may reduce the development of pain-like behaviors in mice.

Animals↗
PubMed2004

High-efficacy 5-HT1A receptor activation causes a curative-like action on allodynia in rats with spinal cord injury.

The selective, high-efficacy 5-HT(1A) receptor agonist, (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methanone (F 13640) has been reported to produce long-term analgesia in rodent models of chronic nociceptive and neuropathic pain; it also preempts allodynia following spinal cord injury. Here, rats underwent spinal cord injury, fully developed allodynia, and were infused with saline or 0.63 mg/day of F 13640 for 56 days. Infusion was then discontinued, and further assessments of allodynia (vocalization threshold to von Frey filament stimulation, responses to brush and cold) were conducted for another 70 days. F 13640-induced analgesia persisted during this post-treatment period. The data offer initial evidence that high-efficacy 5-HT(1A) receptor activation produces an unprecedented curative-like action on pathological pain.

Analgesics↗
PubMed2004

Comparison of the antinociceptive effect of morphine, methadone, buprenorphine and codeine in two substrains of Sprague-Dawley rats.

Sprague-Dawley rats from two different vendors, Möllegård, Denmark and B&K Universal, Sweden, have been tested for the antinociceptive effect of morphine, methadone, buprenorphine and codeine on the hot plate. Morphine and methadone had significantly weaker effect in Möllegård rats compare to B&K rats. In contrast, the effect of buprenorphine was stronger in Möllegård rats than in B&K rats and the effect of codeine was similar in the two substrains. Plasma levels of morphine, morphine-6-glucuronide, morphine-3-glucuronide, buprenorphine and norbuprenorphine were determined at two time points after drug injection. Möllegård rats had significantly lower mean plasma level of morphine and significantly higher ratio of morphine-3-glucuronide/morphine at 30 min, compared to B&K rats. No difference was seen for the metabolism of buprenorphine in the two substrains. The results suggest that Möllegård rats metabolize morphine to morphine-3-glucuronide to a greater extent than B&K rats, and this may at least partly underlie the substrain difference in the effect of morphine. It is also suggested that the antinociceptive mechanisms of buprenorphne may be different from those of morphine and methadone.

Analgesics↗
PubMed2003

Systemic galnon, a low-molecular weight galanin receptor agonist, reduces heat hyperalgesia in rats with nerve injury.

We have examined the effect of systemically administered galnon, a novel low-molecular weight agonist of galanin receptors, on neuropathic pain-like behaviors in rats after photochemically induced partial nerve injury. Galnon is a galanin receptor ligand with moderate affinity to spinal cord membranes (K(D) of 6+/-0.6 microM). While intraperitoneally applied galnon produced no significant effect on mechanical or cold hypersensitivity, it dose-dependently prolonged heat withdrawal latency in nerve-injured rats. The effect of galnon was more potent on the injured side which has significantly shorter latency than the contralateral side. The anti-hyperalgesic effect of galanon was prevented by intrathecal M35, a galanin receptor antagonist. No side effects, such as sedation or motor impairment, were seen following systemic galnon treatment at the doses used. It is concluded that systemic galnon alleviated heat-hyperalgesic response in rats with partial sciatic nerve injury. This effect was likely to be mediated by activation of spinal galanin receptors.

Animals↗
PubMed2003

A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury.

1. Nitric oxide (NO) participates, at least in part, to the establishment and maintenance of pain after nerve injury. Therefore, drugs that target the NO/cGMP signaling pathway are of interest for the treatment of human neuropathic pain. Various compounds endowed with NO-releasing properties modulate the expression and function of inducible nitric oxide synthase (iNOS), the key enzyme responsible for sustained NO production under pathological conditions including neuropathic pain. 2. With this background, we synthesized a new chemical entity, [1-(aminomethyl)cyclohexane acetic acid 3-(nitroxymethyl)phenyl ester] NCX8001, which has a NO-releasing moiety bound to gabapentin, a drug currently used for the clinical management of neuropathic pain. We examined the pharmacological profile of this drug with respect to its NO-releasing properties in vitro as well as to its efficacy in treating neuropathic pain conditions (allodynia) consequent to experimental sciatic nerve or spinal cord injuries. 3. NCX8001 (1-30 microm) released physiologically relevant concentrations of NO as it induced a concentration-dependent activation of soluble guanylyl cyclase (EC(50)=5.6 microm) and produced consistent vasorelaxant effects in noradrenaline-precontracted rabbit aortic rings (IC(50)=1.4 microm). 4. NCX8001, but not gabapentin, counteracted in a concentration-dependent fashion lipopolysaccharide-induced overexpression and function of iNOS in RAW264.7 macrophages cell line. Furthermore, NCX8001 also inhibited the release of tumor necrosis factor alpha (TNFalpha) from stimulated RAW264.7 cells. 5. NCX8001 (28-280 micromol x kg(-1), i.p.) reduced the allodynic responses of spinal cord injured rats in a dose-dependent fashion while lacking sedative or motor effects. In contrast, gabapentin (170-580 micromol x kg(-1), i.p.) resulted less effective and elicited marked side effects. 6. NCX8001 alleviated the allodynia-like responses of rats to innocuous mechanical or cold stimulation following lesion of the sciatic nerve. This effect was not shared by equimolar doses of gabapentin. 7. Potentially due to the slow releasing kinetics of NO, NCX8001 alleviated pain-like behaviors in two rat models of neuropathic pain in a fashion that is superior to its parent counterpart gabapentin. This new gabapentin derivative, whose mechanism deserves to be explored further, offers new hopes to the treatment of human neuropathic pain.

Acetates↗
PubMed2003

The very-high-efficacy 5-HT1A receptor agonist, F 13640, preempts the development of allodynia-like behaviors in rats with spinal cord injury.

Central neuropathic pain after spinal cord injury (SCI) presents a challenging clinical problem with limited treatment options. [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-([(5-methyl-pyridin-2-ylmethyl)-amino]-methyl)piperidin-1-yl]]-methadone (F 13640) is a recently discovered very-high-efficacy, selective 5-HT1A receptor agonist that produces a remarkably powerful, central analgesia through unprecedented neuroadaptive mechanisms. In a rat model of spinal cord injury pain, we previously found that chronic infusion of F 13640 alleviated pain-like behaviors. Here, we report that infusion of 0.63 mg/day of F 13640 for 8 weeks starting 24 h before the induction of injury significantly attenuates the development of chronic allodynia-like behavior in rats sustaining a photochemically-induced, ischaemic injury of the dorsal laminae of the L3-L5 segments of the spinal cord. Importantly, the preemptive effect of F 13640 persisted for 2 months after treatment was discontinued. The data warrant the study of the possible effects of the early administration of F 13640 in patients sustaining spinal cord injury.

Animals↗
PubMed2003

Flexor reflex excitability in mice lacking galanin receptor galanin-R1.

This study was conducted to examine the excitability of the nociceptive flexor reflex and its sensitization by repetitive stimulation of C-fibers in anesthetized mice that lack the galanin-R1 receptor. Repetitive stimulation of C-fibers induced a gradual increase in reflex magnitude during the stimulation (wind-up), and a subsequent increase in spinal reflex excitability (central sensitization). This occurred in GAL-R1 -/-, GAL-R1 +/-, and +/+ wild-type controls, with no significant differences observed between genotypes. Intrathecal administration of galanin markedly blocked the sensitization following the repetitive stimulation in all three groups. No differences between wild-type or galanin-R1 receptor knockout mice were seen. These results confirm previous studies in rats, showing that intrathecal galanin reduces the central sensitization following wind-up. The present data indicate that this effect is probably mediated by receptors other than GAL-R1.

Analysis of Variance↗
PubMed2003

Comparison of response characteristics of cutaneous mechanoreceptors in normal and neuropathic Sprague-Dawley and spontaneously hypertensive rats.

The activity of single myelinated afferents was recorded from dorsal roots L4-5 in normal Spontaneously Hypertensive rats (SHR) and animals that developed mechanical hypersensitivity following ischemic injury to the sciatic nerve. Control and neuropathic SHRs had significantly higher paw withdrawal threshold to mechanical stimulation than control and neuropathic Sprague-Dawleys (SD). In the SHR rats the mechanical response properties of afferents conducting through the injury site were similar to normals and many of the afferents not conducting through the injury site had spontaneous activity. The only significant difference between the two strains was a faster conduction velocity in afferents recorded from SHR than SD rats. Thus, the behavioral hyposensitivity and less development of mechanical allodynia of SHR rats, compared to SD is not due to differences in the properties of myelinated afferents, but probably involves differences in central inhibitory mechanisms in the two strains.

Animals↗
PubMed2003

Opioid hyperalgesia and tolerance versus 5-HT1A receptor-mediated inverse tolerance.

In addition to analgesia, opioids also produce paradoxical hyperalgesic effects following acute and chronic treatment. In this article, we review the occurrence of this hyperalgesia under several conditions, and discuss the potential mechanisms and clinical implications. We also review recent evidence that paradoxical analgesia and inverse tolerance induced by stimulation of 5-HT(1A) receptors, which is a mirror image of opioid-induced hyperalgesia and tolerance, might achieve clinically significant analgesia in chronic pain.

Analgesics, Opioid↗