Analgesia, enhancement of spinal morphine antinociception, and inhibition of tolerance by ultra-low dose of the α2A-adrenoceptor selective antagonist BRL44408.

Ultra-low doses of non-selective α2-adrenoceptor antagonists augment acute spinal morphine antinociception and block morphine tolerance; however, the receptor involved in mediating these effects is currently unknown. Here, we used tail flick and paw pressure tests on the rat to investigate the acute analgesic and tolerance-inducing effects of spinal morphine and norepinephrine alone or in combination with an ultra-low dose of the α2A-adrenoceptor antagonist, BRL44408. We also assessed the potential antinociceptive effects of BRL44408 alone following spinal administration.

Stereo-selective inhibition of spinal morphine tolerance and hyperalgesia by an ultra-low dose of the alpha-2-adrenoceptor antagonist efaroxan.

Ultra-low doses of alpha-2 (α2)-adrenoceptor antagonists augment spinal morphine antinociception and inhibit tolerance, but the role of receptor specificity in these actions is unknown. We used the stereo-isomers of the α2 adrenoceptor antagonist, efaroxan to evaluate the effect of receptor specificity on the induction of spinal morphine tolerance and hyperalgesia. Tail flick and paw pressure tests were first used to evaluate high dose efaroxan (12.

Intrathecal catheterization influences tolerance to chronic morphine in rats.

We evaluated the antinociceptive effects of acute and chronic morphine administered spinally via lumbar puncture in intrathecally catheterized and sham-surgery rats. The effects of acute morphine did not differ between groups. Catheterized rats developed tolerance to chronic morphine more rapidly, compared with sham and naive rats.

Low dose alpha-2 antagonist paradoxically enhances rat norepinephrine and clonidine analgesia.

Ultralow-dose opioid antagonists prolong opioid antinociception and block tolerance. In this study we determined whether low doses of the α-2 adrenergic receptor (A2-R) antagonist, atipamezole, similarly influenced A2-R-induced antinociception and tolerance. In rats, intrathecal norepinephrine (NE) or clonidine in combination with atipamezole was tested using tail-flick and paw pressure tests.

Neonatal ventral hippocampal lesions in male and female rats: effects on water maze, locomotor activity, plus-maze and prefrontal cortical GABA and glutamate release in adulthood.

Schizophrenia is characterized by diverse behavioural and neurochemical abnormalities that may be differentially expressed in males and females. Male rats with neonatal ventral hippocampal lesions (nVHL) have commonly demonstrated behavioural and neurochemical abnormalities similar to those in schizophrenia. Fewer studies have used female rats.

Attenuation of opioid analgesic tolerance in p75 neurotrophin receptor null mutant mice.

Repeated exposure to opioid drugs can lead to the development of tolerance, which manifests as a reduction in analgesic potency, and physical dependence, a response indicated by a withdrawal syndrome. Accumulating evidence suggests that the nerve growth factor (NGF) family of neurotrophins may have an important modulatory role in the induction of opioid analgesia and opioid addiction. Because neurotrophins universally bind the p75 neurotrophin receptor (p75NTR), we investigated whether the activity of this receptor is involved in the development of opioid analgesic tolerance and physical dependence.

Subchronic MK-801 behavioural deficits in rats: partial reversal by the novel nitrate GT 1061.

Cognitive deficits are a core feature of schizophrenia that may be linked to abnormalities in GABA and nitric oxide (NO). Subchronic treatment with glutamate receptor antagonists produces similar deficits, providing a useful model to examine potential therapeutics. The present study investigated the effects of subchronic MK-801 (intraperitoneally; 0.

Low doses of alpha 2-adrenoceptor antagonists augment spinal morphine analgesia and inhibit development of acute and chronic tolerance.

Background And Purpose: Ultra-low doses of opioid receptor antagonists augment spinal morphine antinociception and block the induction of tolerance. Considering the evidence demonstrating functional and physical interactions between the opioid and alpha(2)-adrenoceptors, this study investigated whether ultra-low doses of alpha(2)-adrenoceptor antagonists also influence spinal morphine analgesia and tolerance.

Experimental Approach: Effects of low doses of the competitive alpha(2)-adrenoceptor antagonists-atipamezole (0.

Augmentation of spinal morphine analgesia and inhibition of tolerance by low doses of mu- and delta-opioid receptor antagonists.

Background And Purpose: Ultralow doses of naltrexone, a non-selective opioid antagonist, have previously been found to augment acute morphine analgesia and block the development of tolerance to this effect. Since morphine tolerance is dependent on the activity of micro and delta receptors, the present study investigated the effects of ultralow doses of antagonists selective for these receptor types on morphine analgesia and tolerance in tests of thermal and mechanical nociception.

Experimental Approach: Effects of intrathecal administration of mu-receptor antagonists, CTOP (0.

Involvement of cannabinoid (CB1)-receptors in the development and maintenance of opioid tolerance.

Sustained exposure to opioid agonists such as morphine increases levels of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn, a response implicated in the development of opioid tolerance and physical dependence. Recent evidence suggests that both the opioid-induced increase in CGRP and the development of opioid physical dependence are suppressed by blockade of spinal cannabinoid (CB1)-receptors. The present study examined whether CB1-receptor activity also has a role in the development of opioid tolerance.

Inhibition of tolerance to spinal morphine antinociception by low doses of opioid receptor antagonists.

Ultra-low doses of opioid receptor antagonists inhibit development of chronic spinal morphine tolerance. As this phenomenon mechanistically resembles acute tolerance, the present study examined actions of opioid receptor antagonists on acute spinal morphine tolerance. In adult rats, administration of three intrathecal injections of morphine (15 microg) at 90 min intervals produced a significant decline of the antinociceptive effect and loss of agonist potency in both the tail-flick and paw-pressure tests.

Spinal modulation of calcitonin gene-related peptide by endocannabinoids in the development of opioid physical dependence.

Studies implicate endocannabinoids in the acute and chronic actions of opioid drugs, including the genesis of physical dependence. Previous evidence suggests that spinal release of calcitonin gene-related peptide (CGRP) and activation of its receptors contribute to opioid physical dependence. The release of CGRP at the spinal level is modulated by cannabinoid (CB1)-receptors.

Excitotoxicity of quinolinic acid: modulation by endogenous antagonists.

Quinolinic acid (QUIN), a product of tryptophan metabolism by the kynurenine pathway, produces excitotoxicity by activation of NMDA receptors. Focal injections of QUIN can deplete the biochemical markers for dopaminergic, cholinergic, gabaergic, enkephalinergic and NADPH diaphorase neurons, which differ in their sensitivity to its neurotoxic action. This effect of QUIN differs from that of other NMDA receptor agonists in terms of its dependency on the afferent glutamatergic input and its sensitivity to the receptor antagonists.

Facilitation of spinal morphine analgesia in normal and morphine tolerant animals by neuropeptide SF and related peptides.

Neuropeptide FF and related synthetic amidated peptides have been shown to elicit sustained anti-nociceptive responses and potently augment spinal anti-nociceptive actions of spinal morphine in tests of thermal and mechanical nociception. Recent studies have described the occurrence of another octapeptide, neuropeptide SF (NPSF) in the spinal cord and the cerebrospinal fluid and demonstrated its affinity for the NPFF receptors. This study examined the effects of NPSF and two putative precursor peptides, EFW-NPSF and NPAF, on the spinal actions of morphine in normal and opioid tolerant rats using the tailflick and pawpressure tests.

The spinal basis of opioid tolerance and physical dependence: Involvement of calcitonin gene-related peptide, substance P, and arachidonic acid-derived metabolites.

Chronic opioid use in the management of pain is limited by development of analgesic tolerance and physical dependence. The mechanisms underlying tolerance-dependence are not entirely clear, however, recent evidence suggests that spinal adaptations leading to increased activity of sensory neuropeptides (calcitonin gene-related peptide (CGRP), substance P) and their downstream signaling messengers derived from metabolism of arachidonic acid: prostaglandins (PG), lipoxygenase (LOX) metabolites, and endocannabinoids, plays an important role in this phenomenon. In this communication we review the evidence implicating these factors in the induction and expression of opioid tolerance and physical dependence at the spinal level.

Cognitive effects of neurotoxic lesions of the nucleus basalis magnocellularis in rats: differential roles for corticopetal versus amygdalopetal projections.

The cholinergic hypothesis states that cholinergic neurons of the basal forebrain nucleus basalis magnocellularis (nbm) that project to cortical and amygdalar targets play an important role in memory. Biochemical studies have shown that these target areas are differentially sensitive to different excitotoxins (e.g.

Involvement of spinal lipoxygenase metabolites in hyperalgesia and opioid tolerance.

This study investigated role of spinal lipoxygenase metabolites in induction of hyperalgesia and development of opioid analgesic tolerance. In the rat, nociception was measured using formalin and tail-flick tests. Intrathecal administration of leukotriene receptor agonist (LTB4) augmented the second phase of the formalin response and marginally increased sensitivity to acute thermal stimulation in the tail-flick test, responses suppressed by 6-(6-(3R-hydroxy-1E,5Z-undecadien-1-yl)-2-pyridinyl)-1,5S-hexanediol (U75302), a leukotriene BLT receptor antagonist.

Inhibition of neurokinin-1-substance P receptor and prostanoid activity prevents and reverses the development of morphine tolerance in vivo and the morphine-induced increase in CGRP expression in cultured dorsal root ganglion neurons.

Chronic treatment with opioid drugs such as morphine leads to the development of tolerance, which manifests as a loss of drug potency. The mechanisms underlying this phenomenon are poorly understood, but recent evidence suggests that increased activity of nociceptive sensory transmitters [calcitonin gene-related peptide (CGRP) and substance P] and other signalling messengers (prostaglandins) contribute to its development. Chronic intrathecal morphine administration to rats for 7 days produced analgesic tolerance.

Spinal administration of lipoxygenase inhibitors suppresses behavioural and neurochemical manifestations of naloxone-precipitated opioid withdrawal.

1. This study investigated the role of spinal lipoxygenase (LOX) products in the induction and expression of opioid physical dependence using behavioural assessment of withdrawal and immunostaining for CGRP and Fos protein expression in the spinal cord. 2.

Localization and modulation of calcitonin gene-related peptide-receptor component protein-immunoreactive cells in the rat central and peripheral nervous systems.

Calcitonin gene-related peptide (CGRP) is widely distributed in the central and peripheral nervous system. Its highly diverse biological activities are mediated via the G protein-coupled receptor that uniquely requires two accessory proteins for optimal function. CGRP receptor component protein (RCP) is a coupling protein necessary for CGRP-receptor signaling.

Neurosteroids and glutamate toxicity in fibroblasts expressing human NMDA receptors.

We characterized glutamate receptor-mediated toxicity in mouse fibroblasts expressing the human NR1a/2A or NR1a/2B NMDA receptor. After induction of NMDA receptors, cells in both lines died over a 24 h time period. This toxicity was associated with a progressive increase in the glutamate content of the media.

Neonatal exposure to the glutamate receptor antagonist MK-801: effects on locomotor activity and pre-pulse inhibition before and after sexual maturity in rats.

Neonatal lesions of the ventral hippocampus in rats lead to post- but not pre-pubertal behavioral changes suggesting adolescent onset of dopaminergic hypersensitivity and providing an animal model of schizophrenia. Neonatal exposure to glutamate receptor antagonists produces accelerated apoptosis leading to neuronal loss in central nervous system structures including the hippocampus. This suggested that neonatal MK-801 might lead to behavioural changes like those reported following ventral hippocampal lesions.

Prior ibuprofen exposure does not augment opioid drug potency or modify opioid requirements for pain inhibition in total hip surgery.

Purpose: In previous animal studies, a prior exposure to non-steroidal anti-inflammatory drugs (NSAID) augmented opioid drug potency. This study was designed to answer the question whether a similar effect can be attained in man. The objective was to use NSAID for preoperative pain reduction and at the same time use the NSAID exposure to reduce opioid requirements for pain inhibition in major orthopedic surgery.

Neuroprotection against ischemic brain injury conferred by a novel nitrate ester.

Nitrates exhibit a selectivity of action in different tissue types not fully recognized: in particular, the neuromodulatory and cardiovascular properties can be dissociated. A novel nitrate showed relatively weak systemic effects, but in the middle cerebral artery occlusion rat model of focal ischemia, reduced the cerebral infarct by 60-70% when administered 4 h after the onset of ischemia.