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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two classes of neurons with distinct responses to opioids have been identified in the rostral ventromedial medulla (RVM), a region with a well-documented role in nociceptive modulation. 'On-cells' are directly inhibited by opioids, and opioids can thus gain access to the modulatory circuitry of the RVM by an action on these neurons. 'Off-cells' are likely to exert a net inhibitory effect on nociceptive processing, and are activated by opioids. Because the opioid activation of off-cells is indirect, it has been proposed that on-cells function as inhibitory interneurons, and that opioid-induced suppression of on-cell firing in turn activates off-cells via disinhibition. The aim of the present study was to test this possibility. We had previously shown that excitatory amino acid (EAA) neurotransmission is crucial to the nocifensor reflex-related on-cell burst. We therefore infused the non-selective EAA receptor antagonist kynurenate (0.5-2 nmol, 200-500 nl) into the RVM while recording activity of on-, off- and neutral cells in lightly anesthetized rats. Kynurenate infusions produced a significant decrease in on-cell firing, with suppression of the on-cell burst. Off-cells nonetheless continued to display a tail flick-related pause in firing. Tail flick latency was used as an index of nociceptive responsiveness, and was unaffected by kynurenate infusions. These results demonstrate that a burst of on-cell firing is not required in order for the off-cell to exhibit a reflex-related pause in discharge, and do not support the proposed crucial role for on-cells as inhibitory interneurons within the RVM. In addition, preferential suppression of on-cell tiring was not associated with an increase in tail flick latency. This suggests that, under the conditions of these experiments, on-cell discharge is not a potent regulator of moment-to-moment variations in nociceptive responsiveness.
Pain 1998 Apr
PMID:Analysis of excitatory amino acid transmission within the rostral ventromedial medulla: implications for circuitry. 958 60

Dysregulation in the gamma motoneuron circuitry is proposed as one mechanism to explain the development of trigger point activity in myofascial pain syndrome. Dysregulation in this context is defined operationally as significantly (and functionally) different levels of electrical activity detected in the same muscle on the left and right sides of the body that is persistently present with movement of that muscle. Neurophysiological concepts as they pertain to muscles and motor control principles are reviewed. Research is integrated that ties together material from diverse fields of psychology and medicine. Dysregulation in the gamma motoneuron circuitry may lead to disinhibition of muscle that causes it to remain hyperactive after contraction, generate excessive electrical activity during movement, and/or inappropriately coactivate with other muscles during movement. Any or all of these phenomena may occur with dysregulation. Such dysregulation may be corrected by learning. Immediate clinical implications are discussed, including the addition of specifically targeted neuromuscular retraining procedures via surface electromyography, as well as some conceptual and research issues that require further clarification.
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PMID:Disinhibition in the gamma motoneuron circuitry: a neglected mechanism for understanding myofascial pain syndromes? 965 11

Administration of sodium nitrite (an NO-generating preparation) doses of 11 mg/kg to rabbits was followed by motor disinhibition, with increases in myogram amplitudes in responses to nonreinforced flashes presented on a background of continuous illumination which served as a conditioned inhibitory stimulus; these changes appeared 1-1.5 h after administration and lasted throughout the 4-h observation period. After sodium nitrite doses of 5.5 mg/kg, responses to conditioned inhibition showed only a tendency to motor disinhibition. These results can be explained in terms of the ability of sodium nitrite to inhibit the function of GABAergic receptors, as development of internal inhibition is accompanied by increased inhibitory hyperpolarization processes in which the GABAergic mediator system is involved. The lower and higher sodium nitrite doses produced no increases in myogram amplitudes in responses to combinations of flashes of light and pain reinforcement, as occurred when these stimuli were presented to controls.
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PMID:Effect of sodium nitrite on the execution of defensive and inhibitory conditioned reflexes. 968 32

We examined two possible mechanisms of neuropathic pain: contribution of adjacent intact nerves and decrease in presynaptic inhibition at the central terminal of the injured primary afferent. To this end, we examined the effects of unilateral L5 spinal nerve ligation, which causes mechanical allodynia and heat hyperalgesia in the ipsilateral hind paw, on gene expression in L4 and L5 dorsal root ganglion (DRG) neurons using in situ hybridization (ISH). Specifically, we examined changes in the expression of messenger RNAs (mRNAs) for neuropeptides which have been reported to be up- or down-regulated in the axotomized DRG neurons and for gamma-aminobutyric acid (GABA)A receptor (GABA(A)-R) subunits which contribute to presynaptic inhibition at the primary afferent terminals. Seven days following ligation, ISH demonstrated an increase in signal intensity for calcitonin gene-related peptide (CGRP) mRNA in the subpopulation of small-to medium-sized L4 DRG neurons ipsilateral to the ligation which were not directly injured as compared to the contralateral side, although the overall percentages and the size distribution of positively labelled neurons for CGRP mRNA were not different between the bilateral L4 DRGs. This suggests that the L4 DRG neurons which express CGRP mRNA constitutively up-regulated the gene expression and the functional importance of these neurons has increased following L5 spinal nerve ligation. However, the mRNAs for other neuropeptides such as preprotachykinin (PPT), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), and galanin (GAL), were not different between the bilateral L4 DRGs. The mRNA for the GABA(A)-Rgamma2 subunit was significantly down-regulated in the medium- to large-sized L5 DRG neurons ipsilateral to the ligation as compared to the contralateral side. GABA(A)-Ralpha2 subunit mRNA also decreased in the ipsilateral L5 DRG neurons but did not reach statistical significance. There was no difference in mRNAs between the bilateral L4 DRGs. These data suggest that the presynaptic disinhibition of the ipsilateral L5 primary afferent terminals may be explained at least partly by the down-regulation of GABA(A)-R following L5 spinal nerve ligation. Thus, both the up-regulation of CGRP in adjacent intact nerves and the decrease in presynaptic inhibition at the central terminal of the injured primary afferent could cause the hyper-excitability of dorsal horn neurons and contribute to the molecular mechanisms of this neuropathic pain model.
Pain 1998 Oct
PMID:Change in mRNAs for neuropeptides and the GABA(A) receptor in dorsal root ganglion neurons in a rat experimental neuropathic pain model. 982 8

In this review we critically appraise the value of some phasic and tonic nociceptive tests as models for differentiating the antinociceptive effects of opioid agonists. Using heat-evoked withdrawal of the hind paw or tail of a rodent, several early studies have assessed the effects of stimulus intensity upon antinociceptive potency of opioid agonists. After intrathecal (i.t.) administration of either morphine or sufentanil, for example, for any incremental change in stimulus intensity, the degree of right shift in the dose-response relationship was greater for morphine than for sufentanil. At first glance, such data appear to provide robust support for the pharmacological model of fractional receptor occupancy (FRO), which, according to the historical tenets of classical receptor theory, describes the relationship between intrinsic efficacy and the total receptor concentration. However, new data which elegantly characterize the relative contribution of small calibre unmyelinated and myelinated nociceptive afferents in mediating thermal-evoked responses challenge the exclusivity of such explanations with origins in classical theory. Within our review we report the results of experiments which provide direct electrophysiological evidence that noxious skin heating at a low rate activates C-polymodal nociceptors, but does not effectively activate A-delta mechanothermal nociceptors. In contrast, a high rate of skin heating activates both nociceptor classes, but produces a more intense activation of A-delta nociceptors that occurs after a shorter onset latency compared with the activation of C-fibre nociceptors. Thus, in direct challenge to the traditional model of FRO, a shift in the dose-response relationship of morphine to the right with a reduction in efficacy, may reflect the limited effectiveness of morphine to attenuate the A-delta-mediated component which assumes increasing dominance at high intensity heating. In our appraisal of other nociceptive models we provide an in-depth characterization of afferent processing in the early neonate rat, in which opioids have been tested in both phasic (tail flick and hot-plate) and tonic (formalin) tests. Afferent processing in this model is typified by several behavioural, anatomical and functional features which, although not pathological, are characteristic of those observed in models of nerve injury using the adult rat. Notably, these features include a lack of segmental inhibition ('disinhibition') and afferent input in large diameter myelinated fibres which make synaptic contacts within superficial laminae of the dorsal horn that in the adult are predominantly nociceptive. Paradoxically, because this paradigm demonstrates increased sensitivity to the antinociceptive effects of opioids it may have special merit as a model of tonic pain. It was recently announced that the i.t. administration of pertussis toxin (PTX) caused hyperalgesia and allodynia that appears similar to the symptoms reported by patients suffering from neuropathic pain. Unlike the effects of other opioids so far tested, buprenorphine-induced antinociception is not blocked in this model. This is an exciting finding and provides new optimism that some opioids, notably buprenorphine, may have a special role in managing some types of neuropathic pain.
Pain 1998 Nov
PMID:Some new insights into the effects of opioids in phasic and tonic nociceptive tests. 983 18

Migraine sufferers have abnormal cerebral information processing and personality disorders, post-traumatic headache sufferers also have some personality changes. We therefore, studied intensity dependence of auditory evoked potentials, Plutchik-van Praag's depression inventory, Zuckerman's sensation seeking scales and Zuckerman-Kuhlman's personality questionnaire in patients suffering from migraine without aura (n = 26) and chronic post-traumatic headaches (n = 26) as well as in healthy volunteers (n = 30). The migraine group showed significantly increased neuroticism-anxiety than controls, increased intensity dependence of N1-P2, and decreased thrill and adventure score compared with the controls and post-traumatic headaches. The post-traumatic headache had significantly increased depression compared with the controls, and increased disinhibition compared with the controls and migraines. This study demonstrates that the two headache types have different neurophysiological and personality traits. The pronounced intensity dependence of N1-P2 suggests a cortical potentiation response, together with a decreased thrill and adventure seeking, favor a lower serotonergic innervation in migraine. While the elevated disinhibition and depression, as consequences, may be linked with the wide cortical neuronal/axonal degeneration in post-traumatic headache.
Pain 1999 Feb
PMID:Auditory evoked potentials and multiple personality measures in migraine and post-traumatic headaches. 1006 69

We studied the effect of unilateral ligation of two spinal nerves on behavioral pain responses evoked by various types of cutaneous stimuli in the adult rat. Furthermore, we determined the effect of spinal nerve ligation on morphology of the peripheral nerves. The most consistent behavioral finding (83%) was a marked decrease in monofilament-induced hindlimb withdrawal thresholds (mechanical allodynia) ipsilateral to the spinal nerve ligation. This mechanical allodynia was observed as early as during the 1st post-operative day and it persisted up to 2 months (the maximum length of the observation period). In contrast, hyperalgesia to noxious mechanical stimulation (Randal-Sellitto test) was not observed in allodynic rats until the 3rd post-operative day. In a minority of rats (13%), spinal nerve ligation-induced mechanical hyperalgesia without a concomitant mechanical allodynia. There was no corresponding heat hyperalgesia in the injured hindlimb (hot water immersion-, radiant heat- or hot-plate-induced hindlimb withdrawal tests). In contrast, hypoalgesia to heat was observed on the 1st postoperative day, but not later. Neuropathological analysis of the peripheral nerves revealed a dramatic decrease in the number of myelinated nerve fibers distal to the spinal nerve ligation site. The results support the previous evidence indicating that ligation of spinal nerves induces a marked allodynia to mechanical stimulation. However, this mechanical allodynia may differentially dissociate from mechanical and thermal hyperalgesia at various post-operative time points. The marked mechanical allodynia together with a dramatic decrease in the number of myelinated nerve fibers is paradoxical, since the activation of myelinated nerve fibers by monofilaments produced abnormally strong behavioral responses. This paradox may be explained by spinal nerve ligation-induced amplification or disinhibition of tactile signals at central levels.
Pain 1999 Mar
PMID:Spinal nerve ligation-induced neuropathy in the rat: sensory disorders and correlation between histology of the peripheral nerves. 1020 28

Successive inhibitory, excitatory, inhibitory and excitatory reflexes (the Q, R, S and T waves of the post-stimulus electromyographic complex (PSEC)), evoked by applying non-painful taps to an incisor tooth, were recorded from the jaw-closing muscles of 15 subjects. The effects on these reflexes of the subjects undertaking mental exercises (MEx) in the form of arithmetic calculations were compared with those of remote noxious stimulation (RNS; application of 3 degrees C to a hand). This was done to investigate whether the previously established effects of RNS were likely to be related to a change in the subject's mental state and/or to direct nociceptive mechanisms. Both MEx and RNS caused increases in EMG activity around the Q-R and S-T transitions of the PSEC, which resulted principally from shortenings of the inhibitory Q and S waves. Reducing the intensity of the tap stimuli, which mimicked condition-induced disinhibition, caused shortenings of the inhibitory waves at latencies similar to the shortenings induced by MEx or RNS. The magnitude of the RNS-induced effect on the ST segment of the PSEC was greater (P<0.01) than that on the QR segment. By contrast, MEx induced similar effects on both segments. Regression analyses were performed for the relationship between condition-induced changes in amplitude of the excitatory waves and their control amplitudes. These analyses were performed to reveal any condition-induced inhibition or facilitation of the tap-induced influences on the motoneurons. Overall, the evidence suggested that: (1) mental exercise induced a similar degree of inhibition of the two tap-induced inhibitory jaw reflexes and a facilitation of the excitatory ones, and (2) remote noxious stimulation induced an inhibition of the second tap-induced inhibitory reflex which was greater than that of the first one, and an inhibition of the first excitatory reflex. Thus, although factors related to altered mental activity could play a role in the modulation of jaw reflexes by RNS, the differences between the effects of MEx and RNS suggest that alternative or complementary mechanisms are also likely to be involved.
Pain 2000 Feb
PMID:Mechanisms underlying the effects of remote noxious stimulation and mental activities on exteroceptive jaw reflexes in man. 1066 24

We have used contrast media-enhanced perfusion magnetic resonance imaging MRI to measure regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), regional mean transit time (rMTT) and regional cerebrovascular resistance (rCVR) in volunteers at baseline and during infusion of remifentanil (0.1 microgram kg-1 min-1). Remifentanil increased rCBF and rCBV in white and grey matter (striatal, thalamic, occipital, parietal, frontal) regions, with a parallel decrease in rMTT in those regions with the exception of occipital grey matter. rCVR was decreased in all regions studied. The relative increase in rCBF was greater than that in rCBV. Cerebral haemodynamics were increased significantly in areas less rich in mu-opioid receptors with a tendency towards more pronounced increases in rCBF and rCBV in pain-processing areas. Furthermore, interhemispheric differences in rCBF, rCBV and rMTT found prior to drug administration were almost eliminated during infusion of remifentanil. We conclude that, apart from direct and indirect cerebrovascular effects of remifentanil, these findings are consistent with cerebral excitement and/or disinhibition.
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PMID:Low-dose remifentanil increases regional cerebral blood flow and regional cerebral blood volume, but decreases regional mean transit time and regional cerebrovascular resistance in volunteers. 1099 24

This study used concordant behavioral and electrophysiological approaches to examine the actions of the prototypic kappa opioid receptor agonist U69593 in the rostral ventromedial medulla (RVM). In vitro whole-cell voltage clamp recordings indicated that bath application of U69593 produced outward currents in primary cells in the RVM. In secondary cells, which comprised 80% of the population, U69593 produced a concentration-dependent and norbinaltorphimine (norBNI)-reversible inhibition of evoked excitatory postsynaptic currents (EPSCs) in the absence of any postsynaptic effect. U69593 also decreased the frequency, but not the amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in secondary cells. The inhibition of excitatory inputs to secondary cells would be consonant with disinhibition of primary cells and the production of antinociception. Consistent with this expectation, the activation of kappa opioid receptors in the RVM by microinjection of U69593 produced a dose-dependent increase in paw-withdrawal latency that was antagonized by norBNI. Furthermore, microinjection of norBNI in the RVM antagonized the increases in paw-withdrawal latency and hot-plate latency produced by systemically-administered U69593. In contrast, microinjection of norBNI in the RVM did not antagonize the increase in tail-flick latency produced by systemically-administered U69593. Also, microinjection of U69593 in the RVM did not increase tail-flick latency. The highly test-dependent nature of U69593's effects suggests that the mechanisms by which neurons in the RVM modulate thermal nociceptive responses evoked from the tail and hindpaw are not uniform. Collectively, these data suggest that the RVM is a primary site of action for the antinociceptive actions of kappa opioid receptor agonists and that the mechanism most likely involves a presynaptic inhibition of excitatory inputs to secondary cells. Thus, disinhibition of pain inhibitory neurons in the RVM is likely to be a common mechanism by which opioid receptor agonists produce antinociception, whether by the direct inhibition of inhibitory secondary cells, as in the case of mu opioid receptor agonists, or by a reduction in the excitatory drive to these neurons, as in the case of kappa opioid receptor agonists.
Pain 2001 Apr
PMID:A cellular mechanism for the antinociceptive effect of a kappa opioid receptor agonist. 1127 96


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