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P M Dougherty

Publications and source records attributed to P M Dougherty.

At least 73 records · Page 4Linked to original sources
PubMed1992

Responses of spinothalamic tract neurons to mechanical and thermal stimuli in an experimental model of peripheral neuropathy in primates.

1. An experimental peripheral neuropathy (EPN) was induced in three monkeys (Macaca fascicularis) by ligation of spinal nerve L7. Behavioral responses to innocuous mechanical stimuli were tested before and after the surgery. Two weeks after the nerve ligation, the activity of spinothalamic tract (STT) neurons was recorded on both sides of the spinal cord with the animal under general anesthesia. Responses of the STT neurons to the following stimuli applied to the skin were recorded: graded mechanical stimuli (brush, press, pinch and squeeze), von Frey filaments of different bending forces (0.077-19.05 g), 5-s heat stimuli ranging from 39 to 53 degrees C, and 15 s cold stimuli (32-8 degrees C). 2. Innocuous mechanical stimulation of the foot did not evoke hindlimb withdrawal in the animals before surgery. Within 24-48 h after nerve ligation, the animals showed hindlimb withdrawal to the same innocuous stimuli. This behavior was more pronounced on the side of the ligation than on the sham-operated side and more frequent during the second week after the surgery. 3. Responses of 51 STT neurons recorded on the side of the ligation (EPN all group) were compared with responses of 33 STT cells recorded on the sham-operated side (control group) and with records from STT neurons in unoperated animals obtained earlier (reference group). Neurons from the EPN all group were divided into two sets according to their rostrocaudal location (EPN R, rostral to L6/7 border, n = 40; EPN C, caudal to L6/7 border, n = 11). 4. Neurons from the EPN all and EPN R groups had significantly higher background frequencies than those from the control and reference groups. Innocuous brush stimuli evoked mean discharge frequencies of approximately 35 Hz in EPN R neurons and only approximately 15 Hz in both control and reference groups. Increased responsiveness of EPN R neurons to innocuous stimuli was also demonstrated by lower thresholds and higher discharge frequencies to von Frey filament stimulation and by discriminative analysis of the responses evoked by graded mechanical stimuli. 5. The responses of the EPN R neurons to heat stimulation of the skin showed decreased thresholds and increased responses to suprathreshold stimuli, resulting in a significant leftward shift of the stimulus-response curve compared with both reference and control groups. The neurons from the control group showed responses comparable to reference group values. 6. Neurons from the reference group tested with the cooling stimuli showed no evoked response above background.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

The role of NMDA and non-NMDA excitatory amino acid receptors in the excitation of primate spinothalamic tract neurons by mechanical, chemical, thermal, and electrical stimuli.

The role of excitatory amino acids (EAAs) in the excitation of monkey spinothalamic tract (STT) neurons following activation of cutaneous primary afferent fibers by noxious and non-noxious stimuli was investigated. The responses of STT neurons to either NMDA or non-NMDA EAA ligands were blocked by infusion of specific antagonists through a microdialysis fiber into the region surrounding the cells. Our results show that blockade of non-NMDA receptors results in a nearly complete elimination of the responses of STT neurons to all stimuli. Blockade of NMDA receptors results in an attenuation of the responses to noxious stimuli but, in addition, prevents the development of the sensitization of STT neurons that is often observed after intradermal injection of capsaicin. These observations further support a role of EAAs in the transmission of sensory information from primary afferent fibers to dorsal horn neurons and a role for NMDA receptors in the generation of hyperalgesia.

2-Amino-5-phosphonovalerate↗
PubMed1992

Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany capsaicin-induced sensitization in the monkey.

Sensitization of the responses of dorsal horn neurons to mechanical stimulation may play a role in the generation of hyperalgesia. Intradermal injection of capsaicin (CAP) provides a model of experimental hyperalgesia that possesses a component of allodynia. This hyperalgesia is produced by chemical stimulation of C-fibers, leading to sensitization of dorsal horn neurons, including spinothalamic tract (STT) cells. The changes in the physiological responses of STT neurons following intradermal CAP in monkeys parallel the acute pain and hyperalgesia produced by intradermal CAP in humans. The present study addresses the role that excitatory amino acids (EAAs) may play in the sensitization of STT neurons by intradermal CAP. Our results show that the background discharge rate and the responses of STT cells to mechanical stimulation increase following intradermal CAP. In addition, the responses of the sensitized cells to one or more iontophoretically released EAA agonists, including NMDA, glutamate, aspartate, kainate, DL-alpha-amino-3-hydroxy-5-methyl-isoxazoleproprionic acid, and/or quisqualate, increase following intradermal CAP. It is proposed that an increase in the responses of STT neurons to EAAs contributes to the hyperalgesia produced by this noxious chemical stimulus.

Amino Acids↗
PubMed1991

Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury.

The change in staining density of glial fibrillary acidic protein (GFAP) was analyzed in rats that sustained a chronic constriction injury produced by sutures tied loosely around one sciatic nerve. This injury model of peripheral neuropathy resulted in a behavioral hyperalgesia evidenced by a decrease in mean foot withdrawal latency to radiant heat. Increased GFAP immunostaining was observed in the gray matter of the spinal cord ipsilateral to the lesion and specific to spinal segments in which the sciatic nerve is distributed. Elevated GFAP staining density was attributed primarily to hypertrophy of astrocytes rather than their proliferation or migration since counts of astrocyte profiles demonstrated no significant difference when comparing the lesioned to the control side. The magnitude of the increase in GFAP staining correlated with the degree of hyperalgesia. Thus, these data suggest that astrocytes participate in the sequelae occurring in the dorsal horn following constriction injury of a peripheral nerve.

Animals↗
PubMed1991

Changes in lectin, GAP-43 and neuropeptide staining in the rat superficial dorsal horn following experimental peripheral neuropathy.

The density and distribution of reactivity for two lectins (soybean agglutinin (SBA) and RL-29), growth associated protein-43 (GAP-43) and the neuropeptides substance P and calcitonin gene-related peptide were analyzed in the spinal cord dorsal horn of rats with an experimental peripheral neuropathy. Twenty-eight days postsurgery, the density of label for RL-29 and GAP-43 was increased in laminae I and II on the experimental compared to the control side. In contrast, the density of neuropeptide label was decreased in the same region. Furthermore, on the experimental side, the distribution of both SBA and RL-29 reactivity was increased, extending into lamina III. We hypothesize that the increases in density and distribution of reactivity for the lectins and GAP-43, as well as the decreases in neuropeptide reactivity, reflect injury-induced regenerative changes in primary afferent terminals.

Animals↗
PubMed1991

Neuroma formation and numbers of axons in a rat model of experimental peripheral neuropathy.

Two weeks following chronic partial constriction of rat sciatic nerve, the perineurium was disrupted and a neuroma had formed at the constriction site in all nerves (n = 5). Axon counts demonstrated an 84-99% and a 62-84% decrease in myelinated and unmyelinated axons respectively, distal to the lesion. Distally, the majority of surviving myelinated axons had diameters of less than 5.0 microns. There was considerable disparity in fiber loss from animal to animal, but similar behavioral changes were demonstrated by all animals. These results are discussed with reference to previously published data and possible mechanisms underlying the behavioral manifestations of this neuropathy model.

Animals↗
PubMed1991

Modification of the responses of primate spinothalamic neurons to mechanical stimulation by excitatory amino acids and an N-methyl-D-aspartate antagonist.

Excitatory amino acids (EAAs) are likely to play a key role in sensory transmission in the spinal cord. In the present study, the microiontophoresis technique was used to investigate the effects of L-glutamate (GLUT), N-methyl-D-aspartate (NMDA), and quisqualate (QUIS), as well as an NMDA receptor antagonist, AP-7, on the discharges evoked in nociceptive primate spinothalamic tract (STT) neurons by mechanical stimulation of the skin. Responses to innocuous brushing of the skin were facilitated by GLUT and NMDA (and in some neurons by QUIS) and sometimes reduced by AP-7. GLUT also facilitated the responses to noxious mechanical stimuli. The results are consistent with anatomical evidence for the presence of synapses that contain EAAs on primate STT cells and with the proposal that the co-release of EAAs and neuropeptides may contribute to hyperalgesia.

2-Amino-5-phosphonovalerate↗
PubMed1991

Enhancement of spinothalamic neuron responses to chemical and mechanical stimuli following combined micro-iontophoretic application of N-methyl-D-aspartic acid and substance P.

A role for sensitization of nociceptors in the generation of primary hyperalgesia is well documented. More recent work has begun to define a role of an increased excitability of neurons within the spinal cord in the generation of secondary hyperalgesia. The present study demonstrates increased responses of primate spinothalamic neurons following co-administration of N-methyl-D-aspartic acid (NMDA) and substance P (SP) by micro-iontophoresis. Wide dynamic range and high threshold STT neurons in laminae I-VI showed an increased frequency of discharges following application of NMDA which was characterized by a slow onset to peak discharge rate and a slow return to background levels of discharge. Combined application of NMDA with SP resulted in an enhancement of responses to NMDA that often long outlasted the administration of SP. This increase in response of the cells to NMDA was not produced by repeated application of NMDA alone or following combined application of NMDA with an SP analog. NMDA responses were reduced or prevented in all cases by co-application of an NMDA-receptor antagonist. Finally, long-lasting potentiation of NMDA responses by SP was paralleled by enhanced responses to mechanical stimulation of skin. It is proposed that a mechanism involving the combined synaptic release of excitatory amino acids and peptides leads to secondary hyperalgesia.

Animals↗
PubMed1990

Trans-cranial electrical stimulation attenuates abrupt morphine withdrawal in rats assayed by remote computerized quantification of multiple motor behavior indices.

The goal of the present study was to assess the effects of trans-cranial electrical stimulation on the behavioral signs of the abrupt withdrawal syndrome of rats. However, this goal also necessitated the introduction of an experimental model measuring animal behavior for prolonged periods of time using a computerized animal activity monitoring system to quantify spontaneous motor activities associated with abstinence behavior. Comparable withdrawal severity was obtained by both the activity monitoring system and investigator observation of motor signs of abstinence behavior. Moreover, using this system we demonstrate a time-dependent effect of electrical stimulation in reducing the severity of various indices of motor hyperactivity associated with abrupt morphine withdrawal in rats.

Animals↗
PubMed1990

Microiontophoresis of cocaine, desipramine, sulpiride, methysergide, and naloxone in habenula and parafasciculus.

The effects of microiontophoretically applied cocaine, desipramine (DES), sulpiride (SUL), methysergide (METH), and naloxone (NAL) on the responses of physiologically identified single neurons in the habenula (Hab) and parafasciculus thalami nucleus (PF) were examined in rats. Three cell types were identified in both nuclei on the basis of the responses obtained following noxious stimulation that were classified as "nociceptive-on," "nociceptive-off," and "nonnociceptive" cells. Administration of cocaine generally resulted in a decrease in the firing rate of nociceptive-on and nonnociceptive neurons in both Hab and PF. In contrast, cocaine generally induced an excitation in the baseline firing of the nociceptive-off cells. Cocaine application concomitant with noxious stimulation prevented the evoked responses of the nociceptive-on and the nociceptive-off cells. DES, when applied alone, was found to induce excitation in neuronal discharge of all three cell types in both sites. Combined application of cocaine with DES resulted in no observable change in discharge frequency for the nociceptive-on and nonnociceptive cells, while inducing an additive excitatory effect on the nociceptive-off cells. SUL, in contrast, induced no observable effect on baseline firing when given alone, yet consistently antagonized cocaine-induced effects on all three cell types. Finally, METH and NAL induced no effects on baseline firing or cocaine-induced modifications in neuronal discharge frequency.

Animals↗
PubMed1990

Effects of microiontophoretic application of cocaine, alone and with receptor antagonists, upon the neurons of the medial prefrontal cortex, nucleus accumbens and caudate nucleus of rats.

The spontaneous extracellular electrical activity of 102 neurons, within the caudate nucleus (CN), medial prefrontal cortex (MPC), nucleus accumbens (NAc) and a control site, the lateral thalamic nucleus (LT), was studied. Cocaine depressed spontaneous activity in the majority of the cells studied from all regions except the lateral thalamus. Desipramine, which has been used clinically for the treatment of withdrawal of cocaine, also depressed neuronal activity in the caudate nucleus. In addition, of the three receptor antagonists tested, sulpiride, methysergide and naloxone, only the dopamine antagonist (sulpiride) affected cocaine-induced neuronal responses. This study further emphasizes the emerging importance of midbrain dopaminergic systems in the pharmacological effects of this important drug of abuse.

Animals↗
PubMed1990

Microiontophoretic application of muramyl-dipeptide upon single cortical, hippocampal and hypothalamic neurons in rats.

Muramyl-dipeptide (MDP), a metabolite of bacterial cell walls, has a variety of biological effects, including the induction of acute phase serum glycoproteins and fever, and the promotion of slow wave sleep. Muramyl-dipeptide and other products, derived from immune responses, may act directly in the CNS to recruit secondary autonomic and endocrine responses to disease. To test this hypothesis the properties of single neuron discharges, following local application (microiontophoresis) of MDP within the somatosensory cortex, the dorsal hippocampus and the medial basal hypothalamus were studied in rats. The results obtained from cortical (N = 30), hippocampal (N = 28) and hypothalamic (N = 32) neurons demonstrated a direct effect of MDP upon all three regions of the brain. In addition, MDP modified the responses of these same neurons to morphine. These results support a role of MDP in the process of neuro-immune modulation and further demonstrate an interaction between lymphoid agents and opioids in the CNS.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1990

Muramyl-dipeptide, a macrophage-derived cytokine, alters neuronal activity in hypothalamus and hippocampus but not in the dorsal raphe/periaqueductal gray of rats.

Muramyl-dipeptide (MDP) is derived in vivo by degradation of bacteria cell walls and is the minimum fragment that stimulates the acute phase response to bacterial infection. The present study investigates whether this specific product of an immune response affects central nervous system (CNS) function. To this end, the activity of single neurons within the hypothalamus, hippocampus, and dorsal raphe/periaqueductal gray region prior to and following systemic (i.p.) injection was studied. The results obtained from a total of 120 cells demonstrate that single hypothalamic and hippocampal neurons, sites previously shown to aid in the integration of various environmental stimuli into physiologic processes, alter their neuronal activity in site-specific manners following MDP administration. The specificity of the responses included both the threshold for activation of particular sites, effects of increasing dosages upon response pattern characteristics, and time course to the changes observed. These results therefore suggest that MDPs may play a role in the neuro-immunologic regulatory pathways during the immune response to bacterial infection.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1990

The brain and the immune system: an intact immune system is essential for the manifestation of withdrawal in opiate addicted rats.

Gamma irradiation (500 rad) is often used to suppress the immune system in mice, rats and man. Recently, it was shown that irradiation prior to chronic morphine treatment, dramatically reduces the severity of naloxone-precipitated withdrawal in morphine-dependent animals. In the present study adoptive transfer of 2-6 x 10(8) splenocytes to irradiated rats prior to chronic morphine treatment restored the severity of all withdrawal signs precipitated by naloxone. In contrast, adoptive transfer of fractionated splenocyte subpopulations only partially restored withdrawal severity; and transfer of irradiated splenocytes, red blood cells or diluted numbers of normal splenocytes did not have any observed restorative effect. These findings suggest that specific cellular activities or factors derived from lymphoid cells are required for the expression of opiate withdrawal.

Animals↗
PubMed1989

Trans-cranial electrical stimulation attenuates the severity of naloxone-precipitated morphine withdrawal in rats.

The expression of morphine withdrawal in rats has been demonstrated as dependent upon the integrity of specific brain regions. Focal intracranial electrical stimulation of some of these sites results in the attenuation of withdrawal severity. The present study demonstrates that electrical auricular stimulation, in a paradigm known to attenuate nociceptive responses of several brain nuclei, attenuates the severity of naloxone-precipitated morphine withdrawal in rats. This simple non-invasive treatment, based on long-standing principles of electroacupuncture, may provide a useful adjunct for therapy of the narcotic withdrawal syndrome.

Animals↗
PubMed1989

The immune system and opiate withdrawal.

Whole body exposure to 500 rad ionizing irradiation suppresses the immune system in rats. Moreover, when administered prior to chronic morphine treatment, irradiation exposure also dramatically reduces the severity of naloxone-precipitated withdrawal in morphine dependent animals. The reinstillment of 2-6 x 10(8) normal lymphoid immunocompetent cells to irradiated rats by adoptive transfer prior to chronic morphine treatment restores all withdrawal signs precipitated by naloxone injection. The data suggest that specific cellular activities or factors derived from lymphoid cells are required for the expression of opiate withdrawal, indicating that the immune system participates in the manifestation of opiate dependence.

Animals↗