Biomedical subjects

Z Wiesenfeld-Hallin

Publications and source records attributed to Z Wiesenfeld-Hallin.

At least 19 recordsLinked to original sources

PubMed2003

Hyperalgesia and increased neuropathic pain-like response in mice lacking galanin receptor 1 receptors.

The neuropeptide galanin may have a role in modulation of nociception, particularly after peripheral nerve injury. The effect of galanin is mediated by at least three subtypes of receptors. In the present study, we assessed the nociceptive sensitivity in mice lacking the galanin receptor 1 gene (Galr1) and the development of neuropathic pain-like behaviours after photochemically induced partial sciatic nerve ischaemic injury. Under basal condition, Galr1 knock-out (Galr1(-/-)) mice had shortened response latency on the hot plate, but not tail flick and paw radiant heat, tests. The mechanical sensitivity was not different between Galr1(-/-) and wild type (Galr1(+/+)) mice, whereas the cold response was moderately enhanced in Galr1(-/-) mice. Both Galr1(-/-) mice and Galr1(+/+) controls developed mechanical and heat hypersensitivity after partial sciatic nerve injury. The duration of such pain-like behaviours was significantly increased in Galr1(-/-). The Galr1(-/-) mice and Galr1(+/+) mice did not differ in their recovery from deficits in toe-spread after sciatic nerve crush. The results provide some evidence for an inhibitory function for the neuropeptide galanin acting on galanin receptor 1 (GALR1) in nociception and neuropathic pain after peripheral nerve injury in mice.

Animals↗

PubMed2003

Galanin expression in adult human dorsal root ganglion neurons: initial observations.

Human dorsal root ganglia (DRGs) were obtained during various procedures and processed for single and double in situ hybridisation using oligonucleotide probes complementary to three peptide mRNAs. Some postmortem ganglia were also analysed. In donor (unlesioned) DRGs 12.5% of the neuron profiles (NPs) were galanin mRNA-positive (mRNA(+)), 47.5% calcitonin gene-related peptide (CGRP) mRNA(+) and 32.7% substance P mRNA(+). The corresponding percentages for cervical/thoracic DRGs from patients suffering from severe brachial plexus injury were 32.8%, 57.4% and 34.5%, respectively. In these DRGs a high proportion of the galanin mRNA(+) NPs contained CGRP mRNA and substance P mRNA. In DRGs from a patient with migraine-like pain a comparatively small proportion expressed galanin, whereas in DRGs from a herpes zoster patient galanin mRNA(+) NPs were comparatively more frequent. The results from human postmortem DRGs revealed only weak peptide mRNA signals. The present results demonstrate that galanin is expressed in DRGs not only in a number of animal species including monkey as previously shown, but also in a considerable proportion of human DRG neurons, often together with CGRP and substance P, and mostly in small neurons. Thus, galanin may play a role in processing of sensory information, especially pain, in human DRGs and dorsal horn. However, to what extent a similarly dramatic upregulation of galanin expression can be seen after peripheral nerve lesion in man, as has been reported for rat, mouse and monkey, remains to be analysed.

Adult↗

PubMed2002

Large-amplitude 5-HT1A receptor activation: a new mechanism of profound, central analgesia.

We report the discovery of F 13640 and evidence suggesting this agent to produce powerful, broad-spectrum analgesia by novel molecular and neuroadaptative mechanisms. F 13640 stimulates G(alphaomicron) protein coupling to 5-HT(1A) receptors to an extent unprecedented by selective, non-native 5-HT(1A) ligands. Fifteen minutes after its injection in normal rats, F 13640 (0.01-2.5 mg/kg) decreases the vocalization threshold to paw pressure; 15 min upon injection in rats that are exposed to formalin-induced tonic nociception, F 13640 inhibits pain behavior. The initial hyperalgesia induced by 0.63 mg/kg F 13640 was followed, 8 hrs later, by paradoxical hypo-algesia; 5 mg/kg of morphine produces the opposite effects (i.e., hypo-algesia followed by hyper-algesia). Repeated F 13640 injections cause an increase in the basal vocalization threshold and a reduction of F 13640-produced hyperalgesia; in these conditions, morphine causes basal hyperalgesia and antinociceptive tolerance. Continuous two-week infusion of F 13640 (0.63 mg/day) exerts little effect on the threshold in normal rats, but markedly reduces analgesic self-administration in arthritic rats. F 13640 infusion also decreases allodynic responses to tactile and thermal stimulations in rats sustaining spinal cord or sciatic nerve injury. In these models of chronic nociceptive and neuropathic pain, the analgesia afforded by F 13640 consistently surpasses that of morphine (5 mg/day), imipramine (2.5 mg/day), ketamine (20 mg/day) and gabapentin (10 mg/day). Very-high-efficacy 5-HT(1A) receptor activation constitutes a novel mechanism of central analgesia that grows rather than decays with chronicity, that is amplified by nociceptive stimulation, and that may uniquely relieve persistent nociceptive and neuropathic pains.

Acetates↗

PubMed2002

Decreased inflammatory pain due to reduced carrageenan-induced inflammation in mice lacking adenosine A3 receptors.

Mice with a targeted disruption of adenosine A(3) receptor (A(3)AR) gene were assessed for their nociceptive threshold and for their localized inflammatory response following carrageenan injected into the hindpaw. Under basal conditions no difference was seen between A(3)AR knock-out (A(3)AR(-/-)) and wild-type (A(3)AR(+/+)) mice in nociceptive response to mechanical or heat stimuli. The antinociceptive response to the intrathecal adenosine analogue R-phenylisopropyl adenosine (R-PIA) was also unchanged in the A(3)AR(-/-) mice. In contrast, heat hyperalgesia, plasma extravasation and edema following carrageenan-induced inflammation in the hind paw were significantly reduced in A(3)AR(-/-) mice compared to the A(3)AR(+/+) controls. Thus, mice lacking A(3)AR had deficits in generating the localized inflammatory response to carrageenan, supporting a pro-inflammatory role of A(3)AR in peripheral tissues. However, no evidence for a role of A(3)AR in nociception and the antinociceptive effect of R-PIA was found.

Animals↗

PubMed2001

Neuropeptides in neuropathic and inflammatory pain with special emphasis on cholecystokinin and galanin.

Neuropeptides present in primary afferents and the dorsal horn of the spinal cord have an important role in the mediation of nociceptive input under normal conditions. Under pathological conditions, such as chronic inflammation or following peripheral nerve injury, the production of peptides and peptide receptors is dramatically altered, leading to a number of functional consequences. In this review, the role of two neuropeptides that undergo such altered expression under pathological conditions, cholecystokinin (CKK) and galanin, is reviewed.

Animals↗

PubMed2001

Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor.

Caffeine is believed to act by blocking adenosine A(1) and A(2A) receptors (A(1)R, A(2A)R), indicating that some A(1) receptors are tonically activated. We generated mice with a targeted disruption of the second coding exon of the A(1)R (A(1)R(-/-)). These animals bred and gained weight normally and had a normal heart rate, blood pressure, and body temperature. In most behavioral tests they were similar to A(1)R(+/+) mice, but A(1)R(-/-) mice showed signs of increased anxiety. Electrophysiological recordings from hippocampal slices revealed that both adenosine-mediated inhibition and theophylline-mediated augmentation of excitatory glutamatergic neurotransmission were abolished in A(1)R(-/-) mice. In A(1)R(+/-) mice the potency of adenosine was halved, as was the number of A(1)R. In A(1)R(-/-) mice, the analgesic effect of intrathecal adenosine was lost, and thermal hyperalgesia was observed, but the analgesic effect of morphine was intact. The decrease in neuronal activity upon hypoxia was reduced both in hippocampal slices and in brainstem, and functional recovery after hypoxia was attenuated. Thus A(1)Rs do not play an essential role during development, and although they significantly influence synaptic activity, they play a nonessential role in normal physiology. However, under pathophysiological conditions, including noxious stimulation and oxygen deficiency, they are important.

Adenosine↗

PubMed2001

Intrathecal administration of PNA targeting galanin receptor reduces galanin-mediated inhibitory effect in the rat spinal cord.

Peptide nucleic acids (PNA) are nucleic acid analogues containing neutral amide backbone, forming stable and tight complexes with complementary DNA/RNA. However, it is unclear whether unmodified PNA can efficiently penetrate neuronal tissue in order to act as antisense reagent. Here we show that intrathecal (i.t.) injection of an unmodified antisense PNA complementary to the rat galanin receptor type 1 (GalR1) mRNA is able to block the inhibitory effect of i.t. administered galanin on spinal nociceptive transmission. Autoradiographic ligand binding studies using [125I]galanin show that the unmodified PNA is able to reduce the density of galanin binding sites in the dorsal horn. Thus, unmodified PNA applied i.t. appears to function as an effective antisense reagent in rat spinal cord in vivo.

Animals↗

PubMed2001

Mice over-expressing galanin have elevated heat nociceptive threshold.

The neuropeptide galanin may have a role in modulation of nociceptive input at spinal level. Here we report that mice over-expressing galanin exhibit significant elevation of nociceptive threshold to thermal stimulation in comparison to wild-type mice as assessed by the tail flick and paw heat irradiation tests. No change in response to mechanical or cold stimulation was seen. The elevated heat nociceptive threshold in the galanin over-expressing mice was reversed by intrathecal application of the putative galanin receptor antagonist M-35, galanin-(1-12)-pro-bradykinin-(2-9). The results thus support that galanin has an inhibitory function in rodent spinal cord.

Animals↗

PubMed2001

Reduced antinociception and plasma extravasation in mice lacking a neuropeptide Y receptor.

Neuropeptide Y (NPY) is believed to exert antinociceptive actions by inhibiting the release of substance P and other 'pain neurotransmitters' in the spinal cord dorsal horn. However, the physiological significance and potential therapeutic value of NPY remain obscure. It is also unclear which receptor subtype(s) are involved. To identify a possible physiological role for the NPY Y1 receptor in pain transmission, we generated NPY Y1 receptor null mutant (Y1-/-) mice by homologous recombination techniques. Here we show that Y1-/- mice develop hyperalgesia to acute thermal, cutaneous and visceral chemical pain, and exhibit mechanical hypersensitivity. Neuropathic pain is increased, and the mice show a complete absence of the pharmacological analgesic effects of NPY. In the periphery, Y1 receptor activation is sufficient and required for substance P release and the subsequent development of neurogenic inflammation and plasma leakage. We conclude that the Y1 receptor is required for central physiological and pharmacological NPY-induced analgesia and that its activation is both sufficient and required for the release of substance P and initiation of neurogenic inflammation.

Animals↗

PubMed2001

Microdialysis of galanin in rat spinal cord: in vitro and in vivo studies.

The release of the neuropeptide galanin was measured with microdialysis in the dorsal horn of the rat spinal cord. Recovery of unlabeled galanin-like immunoreactivity (GAL-LI) in vitro was measured with radioimmunoassay (RIA) and was found to be 1.4-1.5%. In vivo galanin level was close to the detection level of the RIA under basal conditions. The peptide was released in the dorsal horn during electrical stimulation of the sciatic nerve. The nerve was stimulated for 30 min at a stimulus strength that activated A- and C-fibers. Thus, release of galanin in the spinal cord of the rat is possible to measure with the microdialysis technique.

Animals↗

PubMed2001

Increased level of cholecystokinin in cerebrospinal fluid is associated with chronic pain-like behavior in spinally injured rats.

Cholecystokinin (CCK) is a physiological antagonist of opioid-mediated antinociception and may be involved in some chronic pain states where opioids have reduced effect. We have previously shown in a rat model of central neuropathic pain after spinal cord injury that blockade of CCK-B receptors lead to marked pain relief. In the present study, we showed that spinally injured rats exhibiting chronic pain-like behaviors (aversive reaction to innocuous mechanical and cold stimulation) had significantly elevated level of CCK-like immunoreactivity in cerebrospinal fluid compared to normal rats or spinally injured rats which did not exhibit pain-like behaviors. The increased level of circulating CCK in the cerebrospinal fluid may thus contribute to the maintenance of chronic pain in these rats by reducing the endogenous inhibitory tone provided by opioid peptides and may be involved in the phenomenon of opioid insensitivity.

Animals↗

PubMed2001

Possible impact of genetic differences on the development of neuropathic pain-like behaviors after unilateral sciatic nerve ischemic injury in rats.

The development of neuropathic-like behaviors following unilateral ischemic injury to the sciatic nerve was examined and compared in four rat strains: Sprague--Dawley (SD), Wistar--Kyoto (WK), spontaneously hypertensive (SHR) and Dark--Agouti (DA). We have also compared two sub-strains of SD rats supplied from two different vendors (SD-BK and SD-DK). The responses to mechanical, heat or cold stimuli of both hind paws were measured before and regularly after injury for up to 10 weeks. Spontaneous paw lifting and changes in paw posture after nerve injury were also examined. Significant differences in basal sensitivity to mechanical or heat stimulation were seen among the four rat strain studied with SHR and DA rats being less sensitive than the SD and WK rats. All strains of rats developed bilateral mechanical allodynia and ipsilateral heat hyperalgesia after photochemically-induced nerve ischemia, but the time-course and magnitude of the responses were significantly different among the strains. Again, the SHR and DA were found to be least susceptible to the development of abnormal pain-like responses. Cold allodynia occurred only in WK and SD-BK. SD-DK rats on the other hand developed more severe mechanical allodynia than SD-BK. SHR and DA rats showed less deficits in paw posture after nerve injury whereas spontaneous pain lifting, a measure of possible spontaneous pain, was comparable among all strains. Light microscopic study of the injured sciatic nerve showed comparable nerve damage in SHR, WK and two sub-strains of SD rats. The DA rats however exhibited reduced area of intraneural damage. Finally, electronmicroscopic examination revealed that damage to both myelinated and unmyelinated fibers occurred in this model in all strains. These results showed that normal sensitivity and the development of pain-like response after partial nerve injury differ substantially among different strains of rats, supporting the emerging concept that genetic factors affect pain sensitivity under normal conditions and after nerve injury. The apparent resistance of DA rats to nerve ischemia, however, may suggest that genetic factors not directly related to pain modulation also play a role in the diverse outcomes. Our results indicate that sub-strains of rats also showed variable development of neuropathic pain-like behaviors to both the modality and magnitude of the effect. Thus, controlling sub-strains is also important in experimental studies of neuropathic pain in rats.

Animals↗

PubMed2000

Intracerebroventricular infusion of nerve growth factor induces pain-like response in rats.

New strategies have recently been developed where infusion of neurotrophic factors into the brain can rescue different neuronal populations. However, negative side effects have been observed in clinical trials infusing nerve growth factor (NGF) into the lateral ventricle in man, namely pain. Little is known about pain behavior in animals after intracerebroventricular (i.c.v.) neurotrophic injections. Thus, we have examined the effects of i.c.v. infusion of NGF for 2 weeks on the behavioral response of rats to mechanical, cold and heat stimulation. Seven micrograms/day of NGF elicited a significant decrease in vocalization threshold to mechanical stimulation and a significantly increased response to cold and heat stimuli as compared with control. The concentration of NGF in cerebrospinal fluid (CSF) was significantly increased as compared with non-allodynic rats. The enhanced responses to mechanical and heat, but not to cold, stimulation were significantly reduced by CP-99994, a selective antagonist to tachykinin NK-1 receptors. When NGF was infused into the brain parenchyma (striatum, cortex and septum) no allodynic nor hyperalgesic responses could be detected. These results indicate that in rats i.c.v. but not intraparenchymal infusion of NGF induce mechanical and cold allodynia as well as heat hyperalgesia, which is mediated, at least in part, by activation of NK-1 receptors.

Animals↗

PubMed2000

Repeated administration of systemic gabapentin alleviates allodynia-like behaviors in spinally injured rats.

The effect of systemic gabapentin, a novel antiepileptic and analgesic, was tested on allodynia-like behaviors in spinal cord injured rats. On the first day of treatment 30 mg/kg intraperitoneal gabapentin did not alleviate hyper-reactivity to mechanical and cold stimulation. The allodynia was significantly reduced by 100 mg/kg gabapentin, which however, produced sedation and motor impairments. Repeated administration of 30 mg/kg gabapentin once a day produced a gradually increasing anti-allodynic effect. Total alleviation of mechanical allodynia was observed in most rats after the third administration of gabapentin. Thus, build-up of the antiallodynic effect of gabapentin may develop through a time dependent mechanism or alternatively through a gradual accumulation of the effective central nervous system concentration of the drug.

Acetates↗

PubMed2000

Development of a mouse model of neuropathic pain following photochemically induced ischemia in the sciatic nerve.

A mouse model of neuropathic pain was developed by a photochemically induced ischemic nerve injury in normal male C57/BL6 mice. The ischemia was induced by unilateral irradiation of the sciatic nerve with an argon ion laser after intravenous administration of a photosensitizing dye, erythrosin B. The nerve injury resulted in a significant decrease in withdrawal threshold of the hindpaws to mechanical stimulation with von Frey hairs, as well as increased responsiveness to cold and heat stimulation. The mice, however, did not exhibit overt spontaneous pain-like behaviors. The evoked pain-related behaviors were observed bilaterally, although the ipsilateral changes were greater than on the contralateral side. The extent and time course of the behavioral changes were related to the duration of laser irradiation, with 1-min exposure producing the most consistent effect. Morphological examination at the light microscopic level revealed partial demyelination and axonal degeneration of the large myelinated fibers at the epicenter of the lesion 1 week postirradiation. The extent of the damage was correlated with the duration of irradiation. Injury and loss of unmyelinated fibers were also observed at the electronmicroscopic level. We conclude that an intravascular photochemical reaction leading to ischemia results in graded damage to the sciatic nerve in mice. Moreover, the nerve injury is associated with the development of abnormal pain-related behaviors. Both the behavioral and the morphological changes are correlated with the duration of irradiation. These results establish a mouse model of partial nerve injury with neuropathic pain-like behaviors which may be useful in studies using genetically modified mice.

Animals↗

PubMed2000

Nociceptin/orphanin FQ in spinal nociceptive mechanisms under normal and pathological conditions.

Nociceptin and its receptor are present in dorsal spinal cord, indicating a possible role for this peptide in pain transmission. The majority of functional studies using behavioral and electrophysiological studies have shown that nociceptin applied at spinal level produces antinociception through pre- and post-synaptic mechanisms. The spinal inhibitory effect of nociceptin is not sensitive to antagonists of opioid receptors such as naloxone. Thus, nociceptin-induced antinociception is mediated by a novel mechanism independent of activation of classic opioid receptors. This has raised the possibility that agonists of the nociceptin receptor may represent a novel class of analgesics. Supporting this hypothesis, several groups have shown that intrathecal nociceptin alleviated hyperalgesic and allodynic responses in rats after inflammation or partial peripheral nerve injury. Electrophysiological studies have also indicated that the antinociceptive potency of spinal nociceptin is maintained or enhanced after nerve injury. It is concluded that the predominant action of nociceptin in the spinal cord appears to be inhibitory. The physiological role of nociceptin in spinal nociceptive mechanisms remains to be defined. Moreover, further evaluation of nociceptin as a new analgesic calls the development of non-peptide brain penetrating agents.

Analgesics↗

PubMed2000

The effect of intrathecal endomorphin-2 on the flexor reflex in normal, inflamed and axotomized rats: reduced effect in rats with autotomy.

Endomorphin-2, a newly discovered endogenous opioid peptide and agonist at the mu-opioid receptor, was injected intrathecally in normal rats and animals with unilateral peripheral inflammation or sciatic nerve section and its effect on the nociceptive flexor reflex was analysed. In normal rats, intrathecal endomorphin-2 induced a strong and dose-dependent depression of the reflex, which was naloxone-reversible. The effect of intrathecal endomorphin-2 was fairly brief, lasting for about 20-30 min at the highest dose, 4 microg. The effect of endomorphin-2 in inflamed rats was not significantly different from that in normals. After nerve section some rats developed autotomy behavior. In these rats endomorphin-2 had significantly reduced effect. However, the reflex depressive effect of intrathecal endomorphin-2 was unchanged in axotomized rats without autotomy. It is suggested that intrathecal endomorphin-2 has antinociceptive effect in the rat spinal cord under normal and inflammatory conditions. After peripheral nerve injury the sensitivity to endmorphin-2 may be reduced in rats that exhibit ongoing neuropathic pain-like behaviors.

Analgesics, Opioid↗

PubMed2000

Effect of morphine on cholecystokinin and mu-opioid receptor-like immunoreactivities in rat spinal dorsal horn neurons after peripheral axotomy and inflammation.

In order to further investigate the interaction between the octapeptide cholecystokinin and opioid analgesia in the spinal cord we used double-colour immunofluorescence to examine the anatomical distribution of cholecystokinin and mu-opioid receptors in the dorsal horn, as well as the effect of morphine on cholecystokinin- and mu-opioid receptor-like immunoreactivities following peripheral nerve injury and inflammation. Mu-opioid receptor-like immunoreactivity was present in 65.6% of cholecystokinin-positive neurons in laminae I and II of rat spinal cord. Conversely, 40.4% of mu-opioid receptor-positive neurons contained cholecystokinin-like immunoreactivity. Systemic application of morphine (1, 3 or 10 mg/kg; i.v.) after sciatic nerve section significantly, but reversibly, decreased mu-Opioid receptor-like immunoreactivity in the medial half of lamina II in segment L5 of the ipsilateral dorsal horn, and cholecystokinin-like immunoreactivity was also markedly reduced in the same region. These effects were dose- and time-dependent and could be prevented by naloxone preadministration. In contrast, no significant change in the pattern of distribution or intensity of mu-opioid receptor- and cholecystokinin-like immunoreactivities was observed in intact rats or during peripheral inflammation. These results provide a cellular basis for the interaction of mu-opioid receptors and cholecystokinin at the spinal level by showing a high degree of co-existence of these two molecules in local interneurons, and also show that morphine can induce rapid and short lasting effects on mu-opioid receptors after peripheral nerve injury. The results contribute to our understanding of how endogenous cholecystokinin reduces the analgesic effect of morphine.

Analgesics, Opioid↗