PubMed Health⌕ Search

Biomedical subjects

D J Mayer

Publications and source records attributed to D J Mayer.

At least 37 records · Page 2Linked to original sources
PubMed1993

Patterns of increased brain activity indicative of pain in a rat model of peripheral mononeuropathy.

Regional changes in brain neural activity were examined in rats with painful peripheral mononeuropathy (chronic constrictive injury, CCI) by using the fully quantitative 14C-2-deoxyglucose (2-DG) autoradiographic technique to measure local glucose utilization rate. CCI rats used in the experiment exhibited demonstrable thermal hyperalgesia and spontaneous pain behaviors 10 d after sciatic nerve ligation when the 2-DG experiment was carried out. In the absence of overt peripheral stimulation, reliable increases in 2-DG metabolic activity were observed in CCI rats as compared to sham-operated rats within extensive brain regions that have been implicated in supraspinal nociceptive processing. These brain regions included cortical somatosensory areas, cingulate cortex, amygdala, ventral posterolateral thalamic nucleus, posterior thalamic nucleus, hypothalamic arcuate nucleus, central gray matter, deep layers of superior colliculus, pontine reticular nuclei, locus coeruleus, parabrachial nucleus, gigantocellular reticular nucleus, and paragigantocellular nucleus. The increase in 2-DG metabolic activity was bilateral in most brain regions of CCI rats. However, somatosensory regions within the thalamus and the cerebral cortex were activated in CCI rats. High levels of 2-DG metabolic activity were observed within the cortical hind limb area, ventral posterolateral thalamic nucleus, and posterior thalamic nucleus contralateral to the ligated sciatic nerve, and these levels were higher than ipsilateral corresponding regions in CCI rats. In addition, patterns of increased neural activity found in the brain of CCI rats showed some similarities and differences to those found in the brain of rats exposed to acute nociception induced by noxious heat or formalin stimulation. Thus, these CCI-induced spontaneous increases in neural activity within extensive brain regions of CCI rats previously implicated in sensory-discriminative and affective-motivational dimensions of pain as well as centrifugal modulation of pain are likely to reflect brain neural processing of spontaneous pain. Implications of increased brain neural activity in mechanisms of neuropathic pain are discussed with emphasis on correlations between spatial patterns of altered brain neural activity and pain-related behaviors in CCI rats and clinical symptoms in neuropathic pain patients.

Animals↗
PubMed1992

Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy.

Central activation of excitatory amino acid receptors has been implicated in neuropathic pain following nerve injury. In a rat model of painful peripheral mononeuropathy, we compared the effects of non-competitive NMDA receptor antagonists (MK 801 and HA966) and a non-NMDA receptor antagonist (CNQX) on induction and maintenance of thermal hyperalgesia induced by chronic constrictive injury (CCI) of the rat common sciatic nerve. Thermal hyperalgesia to radiant heat was assessed by using a foot-withdrawal test and NMDA/non-NMDA receptor antagonists were administered intrathecally onto the lumbar spinal cord before and after nerve injury. Four daily single treatments with 20 nmol HA966 or CNQX beginning 15 min prior to nerve ligation (pre-injury treatment), reliably reduced thermal hyperalgesia in CCI rats on days 3, 5, 7 and 10 after nerve ligation. Thermal hyperalgesia was also reduced in CCI rats receiving a single post-injury treatment with HA966 (20 or 80 nmol) or MK 801 (5 or 20 nmol) on day 3 after nerve ligation when thermal hyperalgesia was well developed. In contrast, a single post-injury CNQX (20 or 80 nmol) treatment failed to reduce thermal hyperalgesia or to potentiate effects of HA966 or MK 801 (5 or 20 nmol) on thermal hyperalgesia in CCI rats. Moreover, multiple post-injury CNQX treatments utilizing the same dose regime as employed for the pre-injury treatment attenuated thermal hyperalgesia but only when the treatment began 1 or 24 h (but not 72 h) after nerve ligation.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1992

Pain-related increases in spinal cord membrane-bound protein kinase C following peripheral nerve injury.

Neuropathic pain following nerve injury is thought to involve central nervous system Ca(2+)-mediated neuronal plastic changes. This study provides evidence that induction and/or maintenance of post-injury neuropathic pain behaviors in the rat is associated with increases in membrane-bound protein kinase C (PKC), a Ca(2+)-dependent process known to mediate central nervous system neuronal plasticity. In addition, spinal cord administration of GM1 ganglioside, an intracellular inhibitor of PKC translocation/activation, reverses both increased levels of membrane-bound PKC and pain-related behaviors. Thus, persistent post-injury neuropathic pain may be mediated by the initiation of excitatory neuropathological processes resulting from an increase in membrane-bound PKC.

Animals↗
PubMed1992

Post-injury treatment with GM1 ganglioside reduces nociceptive behaviors and spinal cord metabolic activity in rats with experimental peripheral mononeuropathy.

In a rat model of painful peripheral mononeuropathy, this study examined the effects of post-injury treatment with a monosialoganglioside, GM1, on abnormal nociceptive behaviors and spinal cord neural activity resulting from loose ligation of the rat common sciatic nerve (chronic constrictive injury, CCI). Thermal hyperalgesia and spontaneous pain behaviors of CCI rats were assessed by measuring foot-withdrawal latencies to radiant heat and by rating spontaneous hind paw guarding positions, respectively. Neural activity within different regions of the spinal cord was inferred in both CCI and sham-operated rats by employing the [14C]-2-deoxyglucose (2-DG) autoradiographic technique to measure spinal cord glucose metabolism. Intraperitoneal (i.p.) GM1 treatment (10 mg/kg) initiated 1 h or 24 h after injury and once daily for the first 9 post-injury days reduced thermal hyperalgesia of the hind paw ipsilateral to nerve ligation and lowered spontaneous pain behavior rating scores in CCI rats. Sciatic nerve ligation reliably increased basal 2-DG metabolic activity of CCI rats in all four sampled regions (laminae I-IV, V-VI, VII, VIII-IX) of spinal cord lumbar segments (L2-L5) both ipsilateral and contralateral to nerve ligation 10 days after injury. Consistent with the drug's effects on spontaneous pain behaviors, 10 daily GM1 treatments (10 mg/kg, i.p.) initiated 1 h after nerve ligation reduced spinal cord 2-DG metabolic activity in laminae V-VI and VII ipsilateral to nerve ligation and in all four sampled regions contralateral to nerve ligation. This attenuation of the increased spinal cord glucose utilization that occurs in the absence of overt peripheral stimulation may reflect an influence of GM1 on increased neural activity contributing to spontaneous pain. Since gangliosides are thought to protect neurons from excitotoxic effects of excitatory amino acids, these results suggest that ganglioside treatment may result in attenuation of excitatory neurotoxicity that may occur following peripheral nerve injury. Thus, ganglioside treatment could provide a new approach to the clinical management of neuropathic pain syndromes following peripheral nerve injury.

Animals↗
PubMed1992

Intrathecal GM1 ganglioside and local nerve anesthesia reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy.

Our previous experiments demonstrated that systemic treatment with GM1 ganglioside reduces nociceptive behaviors and spinal cord metabolic activity in a rat model of painful peripheral mononeuropathy produced by experimental sciatic nerve ligation (chronic constrictive injury, CCI). In the present study, we examined the effects of intrathecal (i.t.) GM1 treatment on thermal hyperalgesia and spontaneous pain behaviors resulting from nerve ligation in order to determine the locus of GM1 action. In addition, a local anesthetic agent, bupivacaine, given alone or combined with i.t. GM1, was applied to the injured sciatic nerve to determine if peripheral nerve anesthesia would influence post-injury nociceptive behaviors. Thermal hyperalgesia to radiant heat decreased in a dose-dependent manner when GM1 (10-80 nmol, i.t.) was administered once daily onto the lumbar segments of the spinal cord beginning 1 h after experimental nerve injury and continued for the first 9 days after nerve ligation. Moreover, this GM1 (80 nmol) treatment regimen reliably lowered spontaneous pain behavior rating scores in CCI rats suggesting the possible attenuation of spontaneous pain. The central site of i.t. GM1 action is located at the caudal (probably lumbar) spinal cord, since i.t. injection of 20 nmol GM1 onto the cervical spinal cord did not produce any protective effect. A single perinerve injection of a local anesthetic agent, bupivacaine (0.5%, 0.6 ml), on the 3rd day after nerve ligation reduced thermal hyperalgesia for at least 24 h following injection, a duration longer than that of the local anesthetic action of bupivacaine. Neither a single bupivacaine injection nor four daily i.t.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Local↗
PubMed1992

Intrathecal MK-801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy.

The hyperalgesia and spontaneous pain that occur following peripheral nerve injury may be related to abnormal peripheral input or altered central activity, or both. The present experiments investigated these possibilities by examining the effects of MK-801 (a non-competitive N-methyl-D-aspartate, NMDA, receptor antagonist) and bupivacaine (a local anesthetic agent) on thermal hyperalgesia and spontaneous nociceptive behaviors in rats with painful peripheral mononeuropathy. Peripheral mononeuropathy was produced by loosely ligating the rat's common sciatic nerve, a procedure which causes chronic constrictive injury (CCI) of the ligated nerve. The resulting hyperalgesia to radiant heat and spontaneous nociceptive behaviors was assessed by using a foot-withdrawal test and a spontaneous pain behavior rating method, respectively. CCI rats receiving 4 daily intraperitoneal (i.p.) MK-801 injections (0.03, 0.1, 0.3 mg/kg) beginning 15 min prior to nerve ligation exhibited less hyperalgesia (i.e., longer foot-withdrawal latencies) on days 3, 5, 7, 10, and 15 after nerve ligation as compared to those receiving saline injections. Thermal hyperalgesia also was reduced when a single MK-801 injection was given intrathecally (i.t.) onto the spinal cord lumbar segments on Day 3 after nerve ligation. This effect of postinjury MK-801 treatment was dose-dependent (2.5-20 nmol) and lasted for at least 48 h after injection. Moreover, i.t. injection of MK-801 (10 nmol) reliably lowered spontaneous pain behavior rating scores in CCI rats compared to those in the saline group. The spinal site of MK-801 action is situated within the caudal (probably lumbar) spinal cord, since i.t. injection of MK-801 (10 nmol) onto the spinal cord thoracic segments did not affect thermal hyperalgesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Local↗
PubMed1992

Calcitonin gene-related peptide enhances substance P-induced behaviors via metabolic inhibition: in vivo evidence for a new mechanism of neuromodulation.

The present study examined the effects of intrathecal (i.t.) injection of calcitonin gene-related peptide (CGRP) on caudally directed biting and scratching induced by i.t. substance P (SP), bombesin (BBS), strychnine (STR), and kainic acid (KA). CGRP alone (5.25, 10.5 and 21 nmol) had no effect on these behaviors, but CGRP pretreatment produced a dose-related enhancement of behaviors induced by SP or BBS, but not by KA or STR. 2-Amino-5-phosphonovaleric acid (APV, 25 nmol), a selective N-methyl-D-aspartate (NMDA) receptor antagonist, did not block the CGRP potentiation of SP and BBS induced behaviors. CGRP, however, failed to enhance scratching and biting induced by a SP analogue [pGlu5-Mephe8-MeGly9]SP(5-11) (Dime-C7) that is resistant to enzymatic degradation by SP endopeptidase. These findings demonstrate that CGRP potentiates SP induced behavioral responses via inhibition of neuropeptide degradation and that this mechanism may serve as a physiological mechanism of SP modulation.

2-Amino-5-phosphonovalerate↗
PubMed1992

Pretreatment with gangliosides reduces abnormal nociceptive responses associated with a rodent peripheral mononeuropathy.

A peripheral mononeuropathy was produced in adult male rats by placing loosely constrictive ligatures around the common sciatic nerve. As reported by others, this procedure reliably results in postoperative behavior indicative of hyperalgesia, allodynia, and potentially, spontaneous pain. In these experiments, thermal hyperalgesia was assessed by measuring foot-withdrawal latencies to radiant heat aimed at the plantar surface of rat hind paws. Behaviors potentially indicative of spontaneous pain were assessed by rating spontaneous hind paw guarding positions. Rats with sciatic nerve ligation were divided into 5 groups (n = 6/group). Three groups received injections (i.p.) of either 10, 20 or 40 mg/kg of cerebral ganglioside mixture, GA. The 4th group was injected with 10 mg/kg of the purified ganglioside GM1, and the 5th group received an equal volume of saline. All injections were given daily for 2 days before surgery, the day of surgery and 9 days after surgery. All animals were behaviorally assessed for 2 days prior to surgery, the day of surgery, as well as 1, 3, 5, 7, and 10 days afterwards. All 5 groups had significantly reduced latencies to hind paw withdrawal on the side ipsilateral to sciatic nerve ligation. However, these hyperalgesic responses were significantly attenuated in rats receiving GA or GM1 pretreatment. These data suggest that this animal model of peripheral neuropathic pain is sensitive to pharmacological manipulations useful for understanding mechanisms of neuropathic pain, including mechanisms related to excitotoxic processes. Such studies could lead to development of clinical approaches to treat this disorder.

Animals↗
PubMed1992

Respiratory failure without pulmonary edema following injection of a glutamate agonist into the ventral medullary raphe of the rat.

Injection of ibotenic acid (IA), a glutamate agonist, into the ventral medullary raphe (VMR; especially the nucleus raphe magnus) of the rat produced respiratory failure and death following a predictable course of events. The response to the IA injection was characterized initially by increased respiratory frequency and was followed by pulmonary arterial hypertension, systemic arterial hypoxemia, acidosis, and hypothermia. Within 90 min apnea occurred as a terminal event in all animals. Gravimetric, bronchoalveolar lavage protein, and histological analyses revealed no evidence of pulmonary edema. Intracerebral (VMR) pretreatment with PPP, a sigma receptor agonist, or scopolamine, a muscarinic cholinergic antagonist, prevented pulmonary failure and death even though postmortem histological analysis showed VMR cell loss and gliosis consequent to the cytotoxic IA injection. Based on the results of the study, it is suggested that the VMR has a role in regulation of pulmonary blood flow. Preliminary pharmacological studies suggested that a disruption of glutamatergic and cholinergic mechanisms mediates the lethal pulmonary phenomenon.

Animals↗
PubMed1991

Regional changes in spinal cord glucose metabolism in a rat model of painful neuropathy.

Spinal cord patterns of metabolic activity in a model of neuropathic pain were assessed in unanesthetized rats by the [14C]-2-deoxyglucose (2-DG) technique. Rats used in this procedure had demonstrable thermal hyperalgesia ipsilateral to sciatic nerve ligation and ipsilateral hindpaws that were lifted in a guarded position. The latter indicated possible spontaneous pain. Sciatic nerve ligation produced significant increases in glucose utilization in the dorsal and ventral horns of both sides, with greater activity present on the ipsilateral as compared to the contralateral side. Peak activity was in laminae V-VI, a region involved in nociceptive processing. Thus, a chronic increase in neuronal activity in these regions may reflect spontaneous neuropathic pain.

Animals↗
PubMed1991

Electroacupuncture in rats: evidence for naloxone and naltrexone potentiation of analgesia.

Low frequency electroacupuncture (EA) analgesia has been thought to be mediated by endogenous opioids. Among other lines of evidence, it has been reported that EA stimulation delivered at 2 and 2-15 Hz in rats could be blocked or partially antagonized by naloxone (NAL) and naltrexone (NTX). In contrast, experiments in one of our laboratories (D.J.M.) showed that NAL did not inhibit 2 Hz, and even potentiated 125 Hz EA analgesia. In an attempt to resolve these discrepancies, we conducted joint experiments in the U.S.A. and in China using the methods which previously yielded NAL reversibility of EA analgesia. In no experiment did opiate antagonists block or reduce EA analgesia. On the contrary, we found that, in most experiments, NAL and NTX potentiated 2 and 2-15 Hz EA analgesia respectively. The potentiation occurred independently of laboratory methods, geographic location of the experiment, strain (Chinese or American), tail temperature, sex, and weight of rats. This potentiation suggests the existence of an opioid anti-analgesic system or that NAL and NTX acquired analgesic properties following EA. These results indicate that EA analgesia in rats is a variable phenomenon even when laboratory methods are rigorously replicated. The EA stimulation may activate multiple conflicting neural circuits which interact and ultimately modulate the analgesic outcome.

Aging↗
PubMed1991

Electroacupuncture analgesia in rats: naltrexone antagonism is dependent on previous exposure.

Inhibition of pain by low frequency electroacupuncture (EA) has been thought to be mediated by endogenous opioids. We reported in a previous paper, however, that naloxone (NAL) and naltrexone (NTX) either potentiated or had no effect on analgesia in EA-naive rats, independent of origin (American or Chinese), sex, weight, geographic location (the U.S.A. or China), or numerous variations of experimental methodology. In the present study, we hypothesized that the number of exposures to EA treatment may be responsible for the discrepant effect of opiate antagonists. We found, as previously demonstrated, analgesia in EA-naive rats was potentiated by NTX. After two pre-exposures to EA, however, NTX antagonized analgesia. These results indicate that, in rats: (1) pre-exposure is a key variable for opiate antagonists to produce antagonism or potentiation of analgesia; (2) environmental cues paired with the initial analgesic manipulation may be responsible for converting analgesia from non-opioid to opioid, as already demonstrated with classically conditioned and learned helplessness induced analgesia; and (3) EA analgesia in rats is a multidimensional manipulation which can be influenced by subtle environmental changes.

Analgesia↗
PubMed1991

Electroacupuncture analgesia in naive rats: effects of brainstem and spinal cord lesions, and role of pituitary-adrenal axis.

Recent studies have shown that analgesia is potentiated by naltrexone (NTX) and naloxone (NAL) pretreatment in rats exposed for the first time to electroacupuncture (EA). In the present study, we have investigated the role of the pituitary-adrenal axis and of brainstem and spinal cord structures in EA analgesia and its potentiation by NTX. The pituitary and adrenal glands do not participate in the production of EA analgesia, but may produce a non-opioid substance which interferes with the development of EA analgesia. Spinalization or dorsolateral funiculi lesions blocked EA analgesia, and intrathecal NTX had no effect. These results indicate that supraspinal structures are necessary to produce and potentiate EA analgesia. Contrary to their critical role in morphine and other models of environmentally produced analgesia nucleus raphe alatus and raphe structures dorsal to it are not necessary for the development of EA analgesia. These structures, however, may contain opiate synapses on which NTX may act as an agonist to potentiate analgesia. The various components which appear to participate in the production of EA analgesia imply a complex circuit of pain modulation systems and indicate that an organism can adapt to distinct environmental conditions with versatile means to avoid pain.

Adrenalectomy↗
PubMed1991

Cholecystokinin and its antagonist lorglumide respectively attenuate and facilitate morphine-induced inhibition of C-fiber evoked discharges of dorsal horn nociceptive neurons.

Extracellular single unit recordings were made from dorsal horn nociceptive neurons of intact, urethane-anesthetized rats during controlled electrical stimulation of the hind paw. Neither local superfusion of cholecystokinin octapeptide (CCK; 6.4 pmol to 20 nmol) nor the CCK antagonist lorglumide (LGM; 145 fmol to 145 pmol) significantly altered A- or C-fiber evoked firing or spontaneous activity. Pretreatment with CCK, however, significantly attenuated, whereas LGM enhanced, morphine-induced inhibition of C-evoked firing. These findings provide further evidence that CCK functions as a selective antagonist of opioid-induced analgesia.

Animals↗
PubMed1991

Spatial distribution of nociceptive processing in the rat spinal cord.

1. Quantitative 2-deoxyglucose (2-DG) experiments were undertaken to determine the spatial distribution of nociceptive responses in the rat spinal cord. Twenty unanesthetized, paralyzed rats with T2 transected spinal cords were divided into groups (n = 4) and stimulated with non-noxious (35 degrees C) or graded noxious temperatures (45 degrees, 47 degrees, 48 degrees, and 49 degrees C). Stimulation was delivered by cyclical immersion of one hind paw in a temperature-controlled water bath. 2. When stimulation began, 50 microCi of 2-DG was injected into the rat, and timed sequential blood samples were drawn to monitor plasma glucose and 2-DG levels. On termination of stimulation, spinal cords were removed, sectioned, and prepared for autoradiography. Local rates of spinal cord metabolism were obtained by microcomputer analysis of autoradiographs. 3. Nociceptive stimulation produced increases in glucose utilization in some of the grey matter laminae previously implicated in nociceptive processing. Within the nociceptive range, 49 degrees and 48 degrees C intensities elicited significantly greater responses than did 45 degrees C stimulation. 4. The rostrocaudal spatial distribution of nociceptive responses was most extensive within laminae V-VI with stimulus-evoked metabolic activity extending 9 mm from L2-L5. Similarly, metabolic increases occurred over 7 mm within lamina VII. In contrast, metabolic activity within the upper dorsal horn (laminae I-IV) extended only 3 mm and was limited to L4. Metabolic patterns within laminae VIII-IX sharply differed from those within other laminae in that no increases occurred within L4, although regions of L3 and L5 were responsive to stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Evidence that substance P selectively modulates C-fiber-evoked discharges of dorsal horn nociceptive neurons.

Previous studies suggest that the undecapeptide substance P (SP) functions as a primary afferent neurotransmitter or neuromodulator of nociception which may mediate the slow temporal summation ('windup') of discharges of dorsal horn nociceptive neurons elicited by repetitive stimulation of C-afferents. The present study tested this hypothesis by investigating the effects of local spinal application of SP and an SP antagonist. [D-Pro2,D-Trp7,9]-SP (DPDT), on A- and C-fiber-evoked firing of dorsal horn neurons in an intact, urethane-anesthetized rat preparation. Extracellular single unit recordings from both wide dynamic range and nociceptive specific neurons during controlled repetitive electrical stimulation of the ipsilateral hind paw indicated that SP enhanced C-evoked firing in an apparent dose-related manner (100 greater than 20 = 4 nmol), whereas DPDT inhibited C-evoked discharges with an apparent bell-shaped dose-response (20 greater than 100 = 4 nmol). Neither agent significantly altered either A-evoked or spontaneous activity. In agreement with previous investigators, morphine sulfate also selectively inhibited C-fiber-evoked firing without altering A-fiber-mediated activity, validating the selectivity of our system. These findings provide additional evidence that SP functions as a neuromodulator of primary afferent nociception, and further suggest that the effects of SP are selective to nociceptive transmission mediated by C-fibers.

Action Potentials↗