Biomedical subjects

P N Fuchs

Publications and source records attributed to P N Fuchs.

At least 19 recordsLinked to original sources

PubMed2001

A comparison of chronic aspartame exposure to aspirin on inflammation, hyperalgesia and open field activity following carrageenan-induced monoarthritis.

The purpose of the present study was to investigate whether chronic aspartame exposure possesses analgesic and anti-inflammatory actions in the carrageenan-induced monoarthritis model similar to those properties of aspirin. Prior research demonstrated that aspartame can reduce second phase formalin pain and increase motor activity in arthritic patients. Fifty-eight male Sprague-Dawly rats were treated with aspartame (25, 50, 100 mg/kg) or saline for six days. An additional group of animals received daily injections of saline and on the sixth treatment day, received a 150-mg/kg dose of aspirin 30-minutes prior to behavioral testing. On Day 6, animals received an intra-articular (i.a.) injection of 2% lambda carrageenan (CARR) or an equal volume of saline and were tested four hours later on threshold to mechanical and thermal stimuli, open field activity, and knee joint diameter. Aspirin-treated arthritic animals exhibited significantly less mechanical hyperalgesia and knee joint inflammation compared with vehicle treated arthritic animals. However, aspirin did not reverse thermal hyperalgesia or increase motor activity to control levels. Aspartame did not reduce inflammation, increase motor activity, or attenuate thermal allodynia, but at 50 mg/kg did attenuate mechanical allodynia compared with vehicle treated arthritic animals. The anti-hyperalgesic effect on mechanical hyperalgesia was not seen at 25 mg/kg or 100 mg/kg aspartame. These results suggest that a certain amount of aspartame may provide relief of arthritic pain to a similar degree as aspirin in some individuals. The specific effect of aspartame and aspirin on mechanical hyperalgesia should be considered when these agents are used for the therapeutic treatment of arthritic conditions.

Animals↗

PubMed2001

Low dose aspirin attenuates escape/avoidance behavior, but does not reduce mechanical hyperalgesia in a rodent model of inflammatory pain.

The present experiment examined the effect of aspirin on the escape/avoidance behavioral response to a mechanical stimulus (476 mN von Frey monofilament) in the place escape avoidance paradigm (PEAP) following subcutaneous administration of carrageenan (CARR). Forty-one male Sprague-Dawley rats received subcutaneous injection of CARR or saline in the left hindpaw and 3 1/2 h later were administered aspirin (0, 50 or 150 mg/kg). Thirty minutes later, animals were tested in the PEAP and then the mechanical paw withdrawal threshold was measured. Compared with Saline vehicle-treated controls, all CARR-treated animals displayed hyperalgesia, as reflected by enhanced responding to mechanical stimulation applied to the CARR-injected paw. Mechanical hyperalgesia was significantly reduced by the pre-treatment of 150 mg/kg, but not 50 mg/kg aspirin. In the PEAP, CARR vehicle-treated animals avoided a preferred location of the test chamber that was associated with mechanical stimulation of the hyperalgesic paw. The shift from a preferred dark side of the chamber to the light side was attenuated by pre-treatment with both doses of aspirin (50 and 150 mg/kg). The lack of anti-hyperalgesia and avoidance behavior with 50 mg/kg aspirin suggests a decrease in the aversive nature of mechanical stimulation of the afflicted paw. It is suggested that the mechanisms underlying the affective/motivational dimension of nociception (escape/avoidance) can be dissociated from the processing of nociceptive information related to withdrawal responding.

Animals↗

PubMed2001

Electrolytic lesion of the anterior cingulate cortex decreases inflammatory, but not neuropathic nociceptive behavior in rats.

The present study investigated the effect of lesions of the anterior cingulate cortex (ACC) on mechanical allodynia/hyperalgesia after L5 ligation or on inflammatory nociceptive responses following formalin injection in the rat. For both the neuropathic and inflammatory pain models, three groups of animals were used. The control groups consisted of a group of sham lesioned animals and a group of animals that had unilateral damage to the ACC or unilateral/bilateral damage to surrounding cortical tissue. The third group consisted of animals that had at least 75% bilateral damage of the ACC. Subjects received L5 ligation or a 0.05-ml injection of 1% formalin into the plantar surface of the hindpaw. In contrast to the control groups, bilateral ACC lesions significantly decreased inflammatory nociceptive responses during the prolonged, tonic portion of the formalin test (20-35 min). The difference between the groups was most prevalent in the amount of time spent licking the paw. However, ACC lesions did not significantly attenuate the enhanced mechanical paw withdrawal threshold in the neuropathic nociceptive model. These results suggest a differential role of the ACC in the modulation of different types of pain conditions.

Acute Disease↗

PubMed2001

Heat, but not mechanical hyperalgesia, following adrenergic injections in normal human skin.

The development of adrenergic sensitivity in nociceptors has been suggested as a mechanism of neuropathic pain. We sought to determine if nociceptors in the skin of normal subjects exhibit adrenergic sensitivity. We investigated the effects of intradermal administration of norepinephrine, phenylephrine, and brimonidine on heat pain sensitivity. Norepinephrine and phenylephrine (in concentrations ranging from 0.1 to 10 microM by factors of 10), brimonidine (at 0.01-1 microM), and saline were injected (30 microl volume) in a random, double-blind manner to different sites on the volar surface of the forearm in ten subjects. Before and after the injections, heat testing was performed with a non-contact laser thermal stimulator. Heat pain threshold was measured by means of a 'Marstock' technique in which subjects pressed a reaction time key when they perceived that a slowly increasing heat stimulus (1 degrees C/s ramp from a 36 degrees C base) was painful. In addition, the subjects used magnitude estimation techniques to rate the intensity of pain to a suprathreshold heat stimulus (47 degrees C, 2 s). Mechanical testing was done using 200-microm diameter probes attached to calibrated weights that provided forces over the range of 16-512 mN. The intradermal injections of norepinephrine, phenylephrine and brimonidine produced little evoked pain. However, a dose-dependant decrease in heat pain threshold, but not mechanical pain threshold, was observed. At the highest drug dose injected, all three adrenergic compounds produced a significant decrease in heat pain threshold compared to the saline injection. A significant increase in response to the suprathreshold heat stimulus was also found. One possible explanation for this apparent heat hyperalgesia is that the decrease in perfusion due to the localized vasoconstriction may alter the heat response. However, in control studies we found that the non-adrenergic vasoconstrictors, angiotensin II and vasopressin did not produce heat hyperalgesia at doses that produced comparable decreases in blood flow. In addition, occlusion of blood flow with a blood pressure cuff did not lead to heat hyperalgesia. Thus, the heat hyperalgesia observed with the adrenergic agonists is not due to a decrease in perfusion associated with the injection. These results indicate that alpha(1)- and alpha(2)-adrenoceptor-mediated mechanisms may play a role in sensitization of nociceptors to heat stimuli in normal skin.

Adolescent↗

PubMed2001

The anxiolytic effect of acute ethanol or diazepam exposure is unaltered in mu-opioid receptor knockout mice.

Previous researchers demonstrate an opioidergic involvement in the anxiolytic and rewarding actions of ethanol and diazepam. Therefore, to further characterize the role of the opioid system in the anxiolytic action of ethanol and diazepam, normal (C57BL/6J), hybrid (B6129F1) and mu-opioid receptor knockout mice were given i.p. ethanol (0, 1.0 or 1.6 g/kg) or diazepam (1.5 mg/kg). The anxiolytic properties of these agents were then tested in the elevated plus-maze. Additional ethanol-treated mu-opioid receptor knockout mice (1 g/kg) were pretreated with the kappa-opioid receptor antagonist nor-BNI (0 or 3 mg/kg) to assess the involvement of kappa-opioid activity in ethanol's anxiolytic actions. The anxiolytic action of ethanol and diazepam in the mu-opioid receptor knockout mouse did not differ from the effects obtained in normal mice and pretreatment with nor-BNI did not significantly attenuate ethanol's actions in mu-opioid receptor knockout mice. Thus, the anxiolytic actions of ethanol and diazepam appear to be independent of opioid system activity in the mu-opioid receptor knockout mouse.

Animals↗

PubMed2001

Olanzapine for the treatment of fibromyalgia symptoms.

Fibromyalgia is a chronic condition that is diagnosed primarily by the presence of generalized pain along with tenderness on palpation of certain body regions. Unfortunately, the pharmacological treatment of fibromyalgia remains problematic. Two patients are described who highlight the use of the atypical neuroleptic olanzapine for the control of symptoms related to fibromyalgia. Prior to the use of olanzapine, both patients had received a multitude of treatments, none of which greatly improved their ability to function in daily activities. With olanzapine, both patients reported a significant decrease in pain and marked improvement in daily functioning. In one case, the pain returned during a period of time when olanzapine was discontinued, an effect that was reversed when olanzapine was reintroduced. The paucity of serious side effects (i.e., extrapyramidal signs) with the atypical neuroleptic olanzapine strongly favors further exploration and use of this drug for the treatment of fibromyalgia symptoms.

Antipsychotic Agents↗

PubMed2001

Roles of capsaicin-insensitive nociceptors in cutaneous pain and secondary hyperalgesia.

Polymodal nociceptors respond to mechanical, thermal and chemical stimuli. Whereas sensitivities to heat and to the irritant substance capsaicin have recently been linked via the properties of the vanilloid receptor type 1 receptor ion channel, sensitivity to noxious mechanical stimuli such as the pinpricks used in clinical neurology seems to be unrelated. We investigated the peripheral neural basis of pinprick pain using quantitative psychophysical techniques combined with selective conduction block by nerve compression and selective desensitization by topical capsaicin treatment. Complete A-fibre block by compression of the superficial radial nerve (criterion: loss of first pain sensation) lowered the stimulus-response function for pinprick pain (-82 +/- 6% versus baseline). Topical pretreatment of the skin with a 10% capsaicin cream also lowered the pinprick stimulus-response function (-32 +/- 10%), whereas laser-evoked heat pain was eliminated completely (-96 +/- 2%). Under combined capsaicin desensitization and A-fibre blockade, pinprick pain was eliminated completely (-98 +/- 1%). Intradermal injection of 40 microg capsaicin into normal skin between two skin areas that had been pretreated with either capsaicin cream or vehicle produced secondary hyperalgesia with a 260% enhancement of the stimulus-response function for pinprick pain in both areas. In contrast, axon reflexive flare spread only into the vehicle-treated area. These results suggest that capsaicin-sensitive afferents, including polymodal A-fibre and C-fibre nociceptors, make a small contribution to pinprick pain and that capsaicin-insensitive C-fibres do not contribute significantly to either mechanical or heat pain. Pinprick pain is mediated primarily by capsaicin-insensitive A-fibre nociceptors, which include high-threshold mechanoreceptors and type I mechano-heat nociceptors. In addition, central sensitization to input from these A-fibre nociceptors is the primary mechanism that accounts for the enhanced pain in response to punctate mechanical stimuli in the zone of secondary hyperalgesia. These capsaicin-insensitive A-fibre nociceptors may also mediate hyperalgesia in neuropathic pain.

Adult↗

PubMed2000

Morphine and gabapentin decrease mechanical hyperalgesia and escape/avoidance behavior in a rat model of neuropathic pain.

A behavioral test paradigm that measures the aversive quality of stimulus-evoked pain in an animal model of neuropathic pain (L5 ligation) was tested for sensitivity to (1) different forces (476 and 202 mN) and frequencies (once every 15 or 30 s) of mechanical stimulation to the hyperalgesic paw and (2) different doses of the common antinociceptive compounds morphine (1 and 10 mg/kg) and gabapentin (30 and 90 mg/kg). Compared to non-ligated controls, the greater force (476 mN) and frequency (every 15 s) of mechanical stimulation of the hyperalgesic paw was associated with the greatest degree of escape/avoidance behavior. There was not a significant degree of escape/avoidance behavior at the lowest force (202 mN) and frequency (every 30 s) of mechanical stimulation. Compared to ligated vehicle treated controls, morphine (1 mg/kg) and gabapentin (90 mg/kg) decreased mechanical hyperalgesia and also attenuated the escape/avoidance behavior. The antinociceptive and antiaversive effects were found at doses that did not produce evidence of decreased motor activity. It is concluded that the behavioral test paradigm used to measure the aversiveness of stimulus-evoked nociceptive behavior is sensitive to different degrees of evoked pain and traditional analgesic compounds.

Acetates↗

PubMed2000

Mechanical and thermal hypersensitivity develops following kainate lesion of the ventral posterior lateral thalamus in rats.

Damage to the ventral-posterior lateral nucleus (VPL) of the thalamus or its afferent pathways can produce moderate to severe on-going pain and pain in response to normally innocuous stimuli (allodynia) and hypersensitivity to mildly noxious stimuli (hyperalgesia). The present study measured the responses to mechanical and thermal stimuli before and 2, 8, 24 and 48 h after a kainate-induced lesion of the VPL in male rats. Compared with control animals, hypersensitivity to mechanical stimulation of the hindpaw was apparent by 24 h post-lesion. At 48 h, the frequency of mechanical response increased from a baseline response frequency of 17+/-4.7 to 46+/-11.6%. Thermal withdrawal latencies 48 h after the lesion decreased from a baseline latency of 9.9+/-1.8 to 5.3+/-0.4 s. It is concluded that a neurotoxic lesion of the VPL results in a delayed onset of mechanical and thermal hyperalgesia. This study suggests a potential model for studying the basic mechanisms and potential therapies for central pain syndrome.

Afferent Pathways↗

PubMed2000

Stress-induced analgesia in mu-opioid receptor knockout mice reveals normal function of the delta-opioid receptor system.

Stress-induced analgesia (SIA) was examined in wildtype and mu-opioid receptor knockout mice. We used thermal paw withdrawal (TPW) latency following a continuous 3-min swim in 20 degrees C water, and found a significant increase in TPW latency in both wild-type and knockout mice. Pre-treatment prior to the swim with naltrindole, a selective delta-opioid receptor antagonist, blocked the increase in TPW latency in knockout mice. These results demonstrate an intact delta-receptor-mediated function of a physiologically-released endogenous agonist in the mu-opioid receptor knockout mouse. The present findings are in contrast with previous reports that analgesia induced by exogenous delta agonists is reduced in the knockout mice.

Analgesia↗

PubMed2000

A behavioral test paradigm to measure the aversive quality of inflammatory and neuropathic pain in rats.

The present experiment assessed the aversive quality of neuropathic and inflammatory pain in rats. Compared to sham-treated animals, L5 ligated (neuropathic) and complete Freund's adjuvant (inflammatory)-treated animals displayed an initial period of escape followed by avoidance of a preferred location of the test chamber that was associated with mechanical stimulation of the hyperalgesic paw. The onset of the avoidance behavior occurred during the first 10-15 min of behavioral testing and was maximal at 30 min. It is concluded that animals find mechanical stimulation of the hyperalgesic paw aversive and that this behavioral test paradigm is an additional method that may be used to assess nociception in rat neuropathic and inflammatory models.

Animals↗

PubMed2000

Secondary hyperalgesia persists in capsaicin desensitized skin.

Several lines of evidence suggest that secondary hyperalgesia to punctate mechanical stimuli arises from central sensitization to the input from primary afferent nociceptors. Conventional C-fiber nociceptors respond to heat stimuli and yet heat hyperalgesia is absent in the region of secondary hyperalgesia. This evidence suggests that the central sensitization to nociceptor input does not involve heat sensitive nociceptors. To test this hypothesis, we investigated whether desensitization of heat sensitive nociceptors by topical application of capsaicin led to an alteration in the secondary hyperalgesia. Two 2x2 cm areas on the volar forearm, separated by 1 cm, were treated in 10 healthy volunteers. One of the areas was desensitized by treatment with 10% topical capsaicin (6 h/day for 2 days). The other site served as vehicle control. Hyperalgesia was produced 2 days later by an intradermal injection of capsaicin (50 microg, 10 microl) at a point midway between the two treatment areas. Secondary hyperalgesia to noxious mechanical stimuli was investigated by using a blade probe (32 and 64 g) attached to a computer-controlled mechanical stimulator. In the area of topical capsaicin treatment, there was a marked increase in heat pain threshold and decrease in heat pain ratings indicating a pronounced desensitization of heat sensitive nociceptors. However, touch threshold and pain to pinching stimuli were not significantly altered. The intradermal capsaicin injection led to the development of a similar degree of secondary hyperalgesia at both the vehicle and capsaicin treatment areas. These results indicate that capsaicin insensitive nociceptive afferents play a dominant role not only in normal mechanical pain but also in secondary hyperalgesia to noxious mechanical stimuli.

Administration, Topical↗

PubMed2000

Aspirin attenuates the anxiolytic actions of ethanol.

The present study examined the effect of aspirin on the anxiolytic action of ethanol. Previous research has shown that ethanol reliably produces an anxiolytic effect on rodent's plus-maze performance while aspirin has been demonstrated to attenuate several of ethanol's behavioral actions. Female Sprague-Dawley rats were given s.c. aspirin doses of 0 or 150 mg/kg, followed 30 min later by s.c. ethanol doses of 0, 1.0 or 1.6 g/kg. After 5 min, animals were tested in the elevated plus-maze. Although aspirin did not have a significant effect on anxiety-related behavior, it did attenuate the anxiolytic action of ethanol at the dose of 1.0 g/kg, but not at the 1.6 g/kg dose. Thus, aspirin by itself does not appear to possess anxiolytic actions, but does modify the anxiolytic actions of 1.0 g/kg, but not 1.6 g/kg ethanol.

Animals↗

PubMed1999

Characterization of mechanical withdrawal responses and effects of mu-, delta- and kappa-opioid agonists in normal and mu-opioid receptor knockout mice.

Clinical and experimental observations suggest that opiates can exert different influences on the perception of stimuli from distinct sensory modalities. Thermally-induced nociception is classically responsive to opiate agonists. mu-Opioid receptor-deficient transgenic mice are more sensitive to thermal nociceptive stimuli and morphine fails to attenuate the nociceptive responses to thermal stimuli in these animals. To enhance our understanding of opiate influences on mechanical sensitivity, we have examined withdrawal responses to a sequence of ascending forces of mechanical stimuli in mice with normal (wild type), half-normal (heterozygous) and absent (homozygous) mu-opioid receptor levels. We report data from mice examined without drug pretreatment or following pretreatment with morphine, the selective kappa-opioid agonist, U50488H, and the selective delta-opioid agonist, DPDPE. Saline-pretreated mice of each genotype displayed similar, monotonically increasing frequency of withdrawal responses to the graded stimuli. Subcutaneously administered morphine produced a dose-dependent reduction in withdrawal responses in wild type and heterozygous mice, but had no significant effect in homozygous mice. Intraventricular administration of DPDPE also reduced the frequency of paw withdrawal (FPW) in wild type mice, but not in homozygous mice. In contrast, systemic U50488H produced a dose-dependent attenuation of paw withdrawal in both wild type and homozygous mice. These findings suggest that (1) interactions of endogenous peptides with mu-opioid receptors may not play a significant role in the response to mechanical stimuli in drug-free animals, and (2) deficiency of mu-opioid receptors has no functional consequence on the response to the prototypical kappa-opioid receptor agonist, but decreases responses to the prototypical mu- and delta-opioid receptor agonists.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Sympathectomy decreases formalin-induced nociceptive responses independent of changes in peripheral blood flow.

The present experiments studied the effect of surgical sympathectomy on mechanical paw withdrawal thresholds and formalin-induced pain behaviors (FIPB) and tested if the effect of sympathectomy on FIPB is dependent on changes in peripheral blood flow. Compared to sham-operated animals, surgical sympathectomy decreased second phase FIPB but did not affect paw withdrawal thresholds to mechanical stimuli. In sympathectomized and sham-operated animals, subcutaneous intraplantar injection of the nonadrenergic vasoconstrictor angiotensin II (20 microl, 1 mM) or the nonadrenergic vasodilator hydralazine (20 microl, 1 mM) prior to formalin injection decreased and increased peripheral blood flow, respectively. In sympathectomized animals, pretreatment with angiotensin II inhibited the increase of peripheral blood flow following formalin injection when compared to animals pretreated with saline or hydralazine. In sham-operated animals, pretreatment with hydralazine or angiotensin II did not alter vasodilation after formalin injection when compared to pretreatment with saline. Pretreatment with vasoactive drugs had no effect on the sympathectomy-induced decrease in FIPB. It is concluded that sympathectomy decreases FIPB by mechanisms that are independent of sympathectomy-induced changes in peripheral blood flow. The formalin test is an easy, reliable model that can be used to study the mechanisms by which the sympathetic nervous system modulates pain processing.

Animals↗

PubMed1997

Repeated cold water swim produces delayed nociceptive responses, but not analgesia, for tonic pain in the rat.

Earlier studies have demonstrated that cold water swim (CWS) produces stress-induced analgesia in tests of brief, phasic pain and produces a delayed nociceptive response (DNR) for more prolonged tonic pain. The present study reports the effect of repeated CWS on tonic pain, as measured by the formalin test. One group of rats was exposed to a 3.5-min swim in 2 degrees C water immediately prior to the formalin injection, to a 1.5-min swim at 50 min, and to another 1.5-min swim at 100 min postformalin injection. Compared to the no-swim control group, subjects which received repeated CWS had dramatically altered formalin pain responses. Formalin responses began just over 3 h postformalin injection, peaked at 4 h, and were still present at 5 h. Inspection of individual responses revealed a substantial degree of variability in the onset of responses, although the magnitude and duration of the formalin pain response remained at the same levels as those of control subjects. The lack of a decrease in the magnitude and duration of the delayed formalin responses indicates that repeated CWS does not produce analgesia for tonic pain. The period of stress, therefore, produces pain suppression but not loss of the mechanisms that subsequently underlie the pain. Earlier controls have ruled out peripheral mechanisms (such as retention of the formalin in the paw tissue). Rather, a memory mechanism appears to have been indicated and it is not lost, but persists until it can be manifested. Further research is needed to study the mechanisms responsible for the DNR.

Analgesia↗

PubMed1996

Electrical stimulation of the cingulum bundle and surrounding cortical tissue reduces formalin-test pain in the rat.

Surgical lesions of the cingulum bundle in humans produce marked decreases in severe pain associated with cancer, reflex sympathetic dystrophy and other forms of chronic pain. Similarly, a temporary block of the anterior cingulum bundle in the rat by microinjection of lidocaine produces significant decreases in formalin-pain and reduces autotomy following peripheral neurectomy. The present study explored the effect of electrical stimulation of the cingulum bundle/surrounding cortical tissue (CB/CT) on tonic pain in the rat. Experiment 1 examined changes in formalin-induced pain responses following a 2.5-min period (30 s/min for 5 min) of electrical stimulation of the CB/CT 15 min prior to the formalin injection. The stimulation produced a significant reduction of first-period and second-period pain responses. Experiment 2 examined changes in formalin-induced pain responses following a 2.5-min period (30 s/min for 5 min) of electrical stimulation of the CB/CT 20 min following the formalin injection. The stimulation produced a dramatic reduction in second-period pain responses which persisted for the duration of the 35-min post-stimulation test period. The fact that either electrical stimulation or surgical section of the CB/CT produces pain relief suggests that this region serves a complex role in pain processing. Since the cingulum bundle has major connections with all other structures of the limbic system, it is possible that electrical stimulation disrupts patterned activity in the system, which is known to play an especially important role in the affective-motivational dimension of pain.

Animals↗

PubMed1996

Delayed nociceptive response following cold-water swim in the formalin test: possible mechanisms of action.

Exposure of animals to aversive events produces stress-induced analgesia. A common method of producing stress in animals is the cold-water swim (CWS). The present series of experiments examines the effect of CWS on tonic pain, as measured by the formalin test, and explores possible mechanisms of action. Experiment 1 demonstrates that a 3.5-min swim in 2 degrees C water produces a delayed nociceptive response (DNR), characterized by a prolonged period of no formalin responding which then begins and continues during the time when control animals, which have not received the CWS, are finished responding. The delayed response begins at 50-60 min postformalin injection, peaks at 80 min, and is still present at 120 min. Experiment 2 indicates that paw temperature effects are not responsible for the DNR, although core body temperature effects are a possible mechanism. However, systematic delays in the formalin injection following the CWS (Experiment 3) drastically altered the DNR even though core body temperature remained unchanged, suggesting that a decrease of core body temperature is insufficient to account for the DNR. Experiment 4 demonstrates that the NMDA antagonist MK-801 administered prior to the CWS dramatically reduces the DNR. The present experiment is the first study that reports a delay as long as 60 min in pain responding. It is concluded that the delayed response to formalin injection is the result of complex interactions involving peripheral mechanisms and central neuronal plasticity in which activity initiated by a noxious input persists after the cessation of the input as a consequence of a stressful event such as the cold-water swim.

Animals↗