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

The midbrain periaqueductal gray matter (PAG) is an important region for endogenous pain suppression. Nerve terminals containing opioid peptides and neurotensin (NT), as well as high densities of opioid- and NT-receptors, have been demonstrated in the ventromedial PAG. Local administration of opioids or NT in this region induces antinociception in experimental animals. In the present microdialysis study, the effect of opioids on the release of NT in the ventromedial PAG was investigated. Perfusion of the microdialysis probe with 10 microM morphine induced a significant increase (P < 0.05; n = 5) of the extracellular level of NT-like immunoreactivity (NT-LI), while perfusion with a 10-fold higher concentration of morphine had no significant effect on the NT-LI release in the PAG. Also perfusion of the dialysis probe with the mu-opioid receptor-specific agonist [D-Ala2-N-Me-Phe4-Gly5-ol]-enkephaline (DAGO) (1 or 100 microM) induced a significant (P < 0.05; n = 7-9) increase of the NT-LI level. The increase in NT-LI release in response to 1 microM DAGO was both calcium-dependent and naloxone-reversible. Since opioid agonists generally inhibit neuronal activity, an indirect mechanism, involving inhibition of tonically active inhibitory neurons, e.g. gamma-aminobutyric acid (GABA) neurons, could be of importance for the opioid induced release of NT. However, local administration in the PAG of the GABA(A) antagonist bicuculline (0.1-10 microM) or the GABA(A) agonist muscimol (1-100 microM) had no significant effect on the extracellular NT-LI level in the PAG, suggesting that GABAergic mechanisms are not involved in the opioid-induced release of NT-LI. In conclusion, the present data provide in vivo evidence that mu-opioid receptors mediate stimulation of neurotensin release in the PAG.
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PMID:Opioid-induced release of neurotensin in the periaqueductal gray matter of freely moving rats. 945 3

Increased pain fibre activity in response to tissue injury results in changes in gene expression and prolonged changes in nerves and their environment. The resulting hyperalgesia and prolonged spontaneous pain are due both to increased sensitivity of peripheral nociceptors (primary hyperalgesia) and to faciliated spinal cord transmission (secondary hyperalgesia, receptive field expansion and allodynia). Hyperexcitability of dorsal horn neurones is first triggered by increased neuronal barrage into the central nervous system ("wind-up"), and later by retrograde chemical influences from the peripheral inflammation (central sensitisation). Central transmission and hyperexcitability are mediated by excitatory amino acids (aspartate and glutamate) and by tachykinins (substance P). Normally, the net effect of the activity in a complex network of inhibitory neurones in the spinal cord ("gate control"), driven by descending projections from brain stem sites, is to dampen and counteract the spinal cord hyperexcitability produced by tissue or nerve injury. Thus, peripherally evoked pain impulses pass through a filtering process involving gamma-aminobutyric acid, glycine and enkephalins. The activity of these substances in the spinal cord usually attenuates and limits the duration of pain. In the case of persistent pain, there is evidence of pathological reduction of the supraspinal net inhibitory actions in combination with ectopic afferent input in damaged nerves. Hence, the pathology of chronic pain (neuropathic pain) differs from that of nociceptive pain and conventional pharmacological treatment of chronic central pain is usually less successful than treatment of inflammation-related pain. The many newly discovered mechanisms for the transmission and modulation of pain impulses are characterised by complex activity-dependent plasticity, which means that therapeutic strategies for persistent pain must be adapted to changing targets--either at the site of injury or at other sites in the central nervous system.
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PMID:[Breakthrough in pain research. Charting of the synaptic network may lead to new analgesics]. 946

1. The role of inhibition in control of plateau-generating neurones in the dorsal horn was studied in an in vitro preparation of the spinal cord of the turtle. Ionotropic and metabotropic inhibition was found to condition the expression of plateau potentials. 2. Blockade of gamma-aminobutyric acid (GABAA) and glycine receptors by their selective antagonists bicuculline (10-50 microM) and strychnine (5-20 microM) enhanced the excitatory response to stimulation of the dorsal root and facilitated the expression of plateau potentials. 3. Bicuculline and strychnine also facilitated the generation of plateau potentials in response to depolarizing current pulses, suggesting the presence of tonic ionotropic inhibitory mechanisms in turtle spinal cord slices. 4. Activation of GABAB receptors also inhibited plateau-generating neurones. The selective agonist baclofen (5-50 microM) inhibited wind-up of the response to repeated depolarizations induced synaptically or by intracellular current pulses. 5. Baclofen reduced afferent synaptic input. This effect was not affected by bicuculline or strychnine and was blocked by the selective GABAB receptor antagonist 2-hydroxysaclofen (2-OH-saclofen, 100-400 microM). 6. Postsynaptically, baclofen inhibited plateau properties. Activation of GABAB receptors produced a hyperpolarization (7.0 +/- 0.5 mV, mean +/- S.E.M., n = 29) with an associated decrease in input resistance (22.7 +/- 3.1%, n = 24). These effects were blocked by extracellular Ba2+ (1-2 mM). 7. When the baclofen-induced hyperpolarization and shunt were compensated for by adjusting the bias current and the strength of the stimulus, baclofen still inhibited generation of plateau potentials. Wind-up and after-discharges were also inhibited by baclofen. These effects remained in the presence of tetrodotoxin (1 microM) and were antagonized by 2-OH-saclofen. 8. The inhibition of plateau properties was observed even when the baclofen-induced hyperpolarization and shunt were blocked by Ba2+ and when potassium channels were blocked by Ba2+ (3 mM), tetraethylammonium (TEA, 15 mM) and apamin (0.25-0.5 microM). The baclofen-sensitive component of the plateau potential was reduced by nifedipine (10 microM), suggesting a modulation of postsynaptic L-type Ca2+ channels. 9. We suggest that inhibitory regulation of plateau properties plays a role in somatosensory processing in the dorsal horn. The inhibitory control of wind-up and after-discharges may be particularly significant in physiological and therapeutic control of central sensitization to pain.
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PMID:Inhibitory control of plateau properties in dorsal horn neurones in the turtle spinal cord in vitro. 950 38

Phantom limb and stump pain is a common sequela of amputation. In geriatric patients with an amputated limb and multiple other illnesses, drug therapy may be problematic and invasive techniques may be risky. Interactions between pathophysiological mechanisms in the peripheral and central nervous systems may be responsible for the initiation and maintenance of chronic phantom limb and stump pain. These mechanisms include: (i) peripheral damage to nociceptive fibres and dorsal root ganglion cells, which acquire abnormal sensitivity to mechanical, thermal and chemical stimuli; (ii) the prolonged sensitisation of central nociceptive 'second order' neurons in the dorsal horn of the spinal cord, which become hyperexcitable and start responding to nonnoxious stimuli; and (iii) the degeneration of nociceptive neurons, which may trigger the anatomical sprouting of low threshold mechanosensitive terminals to form connections with central nociceptive neurons. This may subsequently induce functional synaptic reorganisation in the dorsal horn. The provision of a pain-free perioperative interval using regional anaesthetic techniques is likely to reduce the incidence of phantom limb pain. The therapy of manifest pain is difficult, and treatment should start as soon as possible to prevent chronic pain. In the acute state, the infusion of calcitonin and oral opioid analgesics have proven to be helpful, while established phantom limb pain may respond to antidepressants, anticonvulsants and drugs that mimic or enhance gamma-aminobutyric acid function. Pharmacological treatment should be combined with transcutaneous electrical nerve stimulation, sympathetic blockade and psychotherapy. In addition, new therapeutic strategies are now being tested; examples include capsaicin, new anticonvulsants and N-methyl-D-aspartate antagonists. Patients with severe pain should be referred to a pain specialist to ensure optimal and timely interventional pain management.
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PMID:Optimal treatment of phantom limb pain in the elderly. 960 14

Intrathecal (i.t.) administration of the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline enhances pain behaviors in the formalin test. This study examined whether bicuculline also increases the peripheral inflammation induced by formalin. Subcutaneous injection of 0.25 to 5.0% formalin in the plantar surface of one hindpaw of the rat produced a concentration-dependent increase in plasma extravasation as measured by the Evans Blue method. Pretreatment with 0.3 microg i.t. bicuculline neither enhanced nor suppressed formalin-induced plasma extravasation. This dose of bicuculline also did not affect plasma extravasation induced by injection of 3% kaolin/3% carrageenan in the knee of the rat. These data indicate that the enhancement of formalin-induced pain behaviors by i.t. bicuculline is not secondary to enhanced peripheral inflammation, but more likely reflects enhancement of nociceptive transmission in the spinal cord.
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PMID:Intrathecal bicuculline does not increase formalin-induced inflammation. 962 64

Having a differential sensitivity to morphine can distinguish migraine suffers from healthy people who are headache-exempt. The aim of the present study was to investigate whether such an abnormal response to morphine challenge is entirely dependent on opioid receptor activation. A role for excitatory amino acids and gamma-aminobutyric acid has been proposed on the basis of the effect of diazepam. As opposed to naloxone, this gamma-aminobutyric acid agonist was found to inhibit the adverse effects of low doses of morphine in migraine sufferers, while at the same time being able to almost abolish morphine-induced miosis in subjects who underwent a short-lasting chronic pretreatment. The capacity of diazepam either to control the adverse effects of morphine or to induce well-being in subjects known to suffer from a central neurogenic pain such as migraine, is noteworthy even regarding the clinical treatment of other painful conditions, such as deafferentation pain, which is known to be not satisfactorily treated by using morphine.
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PMID:Painful and non-painful effects of low doses of morphine in migraine sufferers partly depend on excitatory amino acids and gamma-aminobutyric acid. 967 25

The chemical structure of gabapentin (Neurontin) is derived by addition of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures. Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. Gabapentin interacts with a high-affinity binding site in brain membranes, which has recently been identified as an auxiliary subunit of voltage-sensitive Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and remains under study. Gabapentin crosses several lipid membrane barriers via system L amino acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity. Although gabapentin may have several different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important.
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PMID:Mechanisms of action of gabapentin. 968 47

In the past 15 years the release of neurotransmitters and their metabolites in the locus coeruleus (LC) has been studied by using three approaches: microdialysis; push-pull superfusion; and voltammetry. These sophisticated techniques, which render it possible to follow the time course and magnitude of neurochemical changes in anaesthetized and conscious animals, have permitted great strides towards understanding neurotransmission in the LC. It appears that noradrenaline, known to be released in distant terminal fields, is also released in the somatodendritic area of LC neurons in response to drugs and physiological stimuli. Furthermore, determination of in vivo release enables the identification of functionally important neurotransmitter systems involved in relaying and integrating information reaching the LC via afferent neurons. As outlined in this review, the release rates of glutamate, aspartate, gamma-aminobutyric acid, glycine, 5-hydroxytryptamine and catecholamines, are modified in particular by arousing and stressful stimuli, pain, changes in cardiovascular homeostasis, as well as during opioid withdrawal or the sleep-wake-cycle. Profound interactions also occur between some of the neurotransmitters released during these situations. It appears that individual stimuli produce distinct neurochemical changes which contribute to the regulation of neuronal LC activity. Stimuli that activate LC neurons, such as pain, fall of blood pressure, noise, opiate withdrawal, do not produce a uniform response but modality-specific release patterns of excitatory and inhibitory neurotransmitters within the LC. From these studies and from existing neuroanatomical and electrophysiological data our knowledge of how neurotransmitters work in concert to regulate the functional state of LC noradrenergic perikarya in physiological and pathophysiological conditions is just emerging.
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PMID:Release of neurotransmitters in the locus coeruleus. 976 Jul 3

Gabapentin (GBP) and S(+)-3-isobutyl-gamma-aminobutyric acid (IBG) are anticonvulsant agents which are effective against many clinical and experimental neuropathic pain states. We examined the efficacy of these agents in a new rat model of secondary mechanical hyperalgesia generated by a mild thermal injury. Under brief halothane anesthesia, an injury was induced by applying one heel to a hot surface (52.5 degreesC) for 45 s. GBP, IBG or saline was injected i.p. just prior to the injury. Mean mechanical withdrawal threshold (MWT) was determined using von Frey hairs before and at 30 min intervals for 3 h following the injury. MWT outside the injury area decreased post-injury (secondary hyperalgesia, allodynia), but primary (site of injury) mechanical hyperalgesia was not observed. Secondary hyperalgesia exhibited a tendency toward recovery over time. Time to onset of the anti-allodynic effect of GBP was 30-60 min. The minimum effective GBP dose was 100 mg/kg; 300 mg/kg GBP totally inhibited the drop in MWT, but was accompanied by pronounced sedation. Anti-allodynic effects of IBG were apparent at the first post-injury measure of MWT (30 min). Thirty milligrams per kilogram was the minimum effective dose; 100 mg/kg IBG totally blocked the allodynia with minimal side effects. Our findings demonstrate a dose-dependent blockade of the mechanical sensitivity caused by a mild thermal injury by both GBP and IBG. Results indicate that IBG is more effective than GBP in this model at doses which do not cause sedation. These observations support the suggested use of these or related gamma-amino acid analogues as an effective treatment for post-operative pain.
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PMID:Systemic gabapentin and S(+)-3-isobutyl-gamma-aminobutyric acid block secondary hyperalgesia. 981 59

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


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