Alpha-lipoic acid mitigates insulin resistance in Goto-Kakizaki rats.

Impaired glucose uptake and metabolism by peripheral tissues is a common feature in both type I and type II diabetes mellitus. This phenomenon was examined in the context of oxidative stress and the early events within the insulin signalling pathway using soleus muscles derived from non-obese, insulin-resistant type II diabetic Goto-Kakizaki (GK) rats, a well-known genetic rat model for human type II diabetes. Insulin-stimulated glucose transport was impaired in soleus muscle from GK rats. Oxidative and non-oxidative glucose disposal pathways represented by glucose oxidation and glycogen synthesis in soleus muscles of GK rats appear to be resistant to the action of insulin when compared to their corresponding control values. These diabetes-related abnormalities in glucose disposal were associated with a marked diminution in the insulin-mediated enhancement of protein kinase B (Akt/PKB) and insulin receptor substrate-1 (IRS-1)-associated phosphatidylinostol 3-kinase (PI 3-kinase) activities; these two kinases are key elements in the insulin signalling pathway. Moreover, heightened state of oxidative stress, as indicated by protein bound carbonyl content, was evident in soleus muscle of GK diabetic rats. Chronic administration of the hydrophobic/hydrophilic antioxidant alpha -lipoic-acid (ALA, 100 mg/kg, i.p.) partly ameliorated the diabetes-related deficit in glucose metabolism, protein oxidation as well as the activation by insulin of the various steps of the insulin signalling pathway, including the enzymes Akt/PKB and PI-3 kinase. Overall, the current investigation illuminates the concept that oxidative stress may indeed be involved in the pathogenesis of certain types of insulin resistance. It also harmonizes with the notion of including potent antioxidants such as ALA in the armamentarium of antidiabetic therapy.

Diabetes attenuates the response of the lumbospinal noradrenergic system to idazoxan.

Allodynia is a common feature of painful diabetic neuropathy. This phenomenon appears to be under endogenous noradrenergic control and can be ameliorated effectively by alpha(2)-adrenoceptor agonists. Accordingly, diabetic lumbospinal noradrenergic dynamics was evaluated using high performance liquid chromatography with electrochemical detector (HPLC-ECD), in vitro ligand binding and RT-PCR-based techniques. Streptozotocin (STZ)-treated and Goto-Kakizaki (GK) diabetic rats were included, respectively, as models for type I (insulin-dependent) and type II (non-insulin-dependent) diabetes mellitus. The data from these studies revealed that lumbospinal norepinephrine (NE) release, as indicated by the 3-methoxy-4-hydroxyphenyl glycol (MHPG)/NE ratio, was decreased as a function of diabetes. Similarly, the binding density of [3H] p-aminoclonidine and the level of expression of mRNA transcripts encoding for the alpha(2A)-adrenoceptor subtype and noradrenergic transporter were also reduced in this disease state. Analogous findings were obtained in non-diabetic Wistar rats rendered hypercortisolemic by the subcutaneous implantation of slow releasing pellets containing a supraphysiological dose of glucocorticoid (GC). Tactile allodynia was consistently observed in STZ- and GC-treated animals. The responsiveness of alpha(2)-adrenoceptors to idazoxan (alpha(2)-adrenoceptor antagonist) indicated a dose-dependent enhancement of noradrenergic transmission in lumbar segments of normal spinal cord. In stark contrast, this neurochemical action of idazoxan was attenuated in diabetic and hypercortisolemic animals. The institution of insulin therapy ameliorated diabetes-related abnormalities in lumbospinal noradrenergic dynamics. Overall, the current finding suggests that diabetic and hypercortisolemic allodynic symptoms may stem from, at least in part, down-regulation of alpha(2)-adrenoceptors in these disease states.

Insulin-like growth factor 1-induced alterations in lumbospinal monoamine dynamics.

A wealth of evidence indicates that insulin-like growth factor (IGF-1) is involved in neurotransmitter release, synaptic plasticity, morphogenesis and regulation of gene expression. RT-PCR and immunocytochemical-based techniques revealed that IGF-1 and its receptor are highly expressed by different neuronal elements of the spinal cord lumbar enlargement. Accordingly, the present study intended to examine lumbospinal monoamine dynamics in the context of the neurotrophic factor IGF-1. Spinal release of norepinephrine (NE) represented by 3-methoxy-4-hydroxyphenylglycol (MHPG)/NE ratio was enhanced by IGF-1. This action of IGF-1 was associated with a similar increase in both tyrosine hydroxylase (TH) immunoreactivity and the level of its mRNA. In contrast, neuronal contents of serotonin and its metabolite 5-hydroxyindoleacetic acid in IGF-1-treated animals remained at control level. Genistein, a tyrosine kinase inhibitor, which by itself had no effect on NE metabolism, abolished the induction effect of IGF-1 on TH and MHPG/NE ratio. Our results suggest that IGF-1 augments the lumbospinal noradrenergic system by an intracellular mechanism involving a receptor-linked tyrosine kinase. The physiological consequences of the IGF-1 actions are discussed in terms of neuroprotection and nociception.

On substance abuse in Kuwait (1992-1997). Evidence from toxicological screening of patients.

PURPOSE: To assess preference for different psychoactive substances and time trends in Kuwait. METHODS: Analysis of urine and blood samples of specimens sent by attending physicians to the only public health reference laboratory for toxicological screening in the country. RESULTS: A total of 28,548 tests were performed on 3781 samples. Cannabinoids were positive in 40% of the tested samples, opiates in 24%, ethanol in 10%, and amphetamines in 5%. Elevated concentrations of methadone, cocaine, and phencyclidine did not exceed 0.1%. About 40% of samples was positive for benzodiazepines, but their therapeutic use obscures the informativeness of this finding. There was a significant increase in the proportion of positive results for ethanol, amphetamines, and benzodiazepines. IMPLICATIONS: It is high time to implement a modern and comprehensive preventive and control program. The tendency to blame the Iraqi invasion for drug addiction has hampered efforts to recognise and address the problem in its entirety.

Spinal cord noradrenergic dynamics in diabetic and hypercortisolaemic states.

Disorders of pain sensation including spontaneous pain, allodynia and hyperalgesia are commonly seen in neuropathic diabetic patients. A wealth of evidence indicates that spinal monoamine systems are implicated in pain modulation but whether abnormalities in these systems underlay such disorders is unclear. The present study was therefore initiated to investigate spinal noradrenergic dynamics during diabetes. Spinal release of norepinephrine (NE) represented by 3-methoxy-4-hydroxyphenylglycol (MHPG)/NE ratio was markedly suppressed in 30-day streptozotocin (STZ)-treated diabetic male and female rats. The density of [3H] p-aminoclonidine binding sites and the level of expression of mRNA encoding for alpha2A-adrenoceptor subtype were also reduced as a function of diabetes. In contrast, an increase in the density of [3H] prazosin binding to spinal synaptosomal membranes was evident in these animals. Clonidine-induced elevation in nociceptive threshold was attenuated in diabetics. Control animals subjected to chronic treatment with a supraphysiological dose of glucocorticoid (GC) exhibited a neurochemical pattern which is similar in many respects to that produced by the diabetic state. Both insulin and the GC receptor blocker, RU 486, restored most of the neurochemical and behavioural abnormalities of diabetes. Overall, the present study supports the concept that a diabetes-related deficit in spinal noradrenergic dynamics may be a reflection of an overactivity of the hypothalamic-pituitary-adrenal axis.

Cooling-induced contraction in ovine airways smooth muscle.

The mechanism of cold-induced bronchoconstriction is poorly understood. This prompted the present study whose aim was to determine the step-wise direct effect of cooling on smooth muscle of isolated ovine airways and analyse the role of calcium in the mechanisms involved. Isolated tracheal strips and bronchial segments were suspended in organ baths containing Krebs' solution for isometric tension recording. Tissue responses during stepwise cooling from 37 to 5 degrees C were examined. Cooling induced a rapid and reproducible contraction proportional to cooling temperature in ovine tracheal and bronchial preparations which was epithelium-independent. On readjustment to 37 degrees C the tone returned rapidly to basal level. Maximum contraction was achieved at a temperature of 5 degrees C for trachea and 15 degrees C for bronchiole. Cooling-induced contractions (CIC) was resistant to tetrodotoxin (1; 10 micrometer), and not affected by the muscarinic antagonist atropine (1 micrometer) or the alpha-adrenergic antagonist phentolamine (1 micrometer), or the histamine H1-antagonist mepyramine (1 micrometer) or indomethacin (1 micrometer). Ca2+ antagonists (nifedipine and verapamil) and Mn2+ raised tracheal but not bronchiolar tone and augmented CIC. Incubation in Ca2+-free, EGTA-containing Krebs' solution for 5 min had no effect on CIC, although it significantly reduced KCl-induced contraction by up to 75%. Cooling inhibited Ca2+ influx measured using 45Ca2+ uptake. Caffeine (100 micrometer) significantly inhibited CIC. The results show that cooling-induced contractions do not appear to involve activation of nerve endings, all surface reception systems or Ca2+ influx. However, CIC is mainly dependent on release of intracellular Ca2+.

Cooling-induced bronchoconstriction: the role of ion-pumps and ion-carrier systems.

The mechanism of cold-induced bronchoconstriction is poorly understood. Our previous results show that cooling-induced contractions (CIC) do not involve activation of cell surface receptor systems nor innervation nor Ca2+ uptake. However, the results show that CIC is mainly dependent on intracellular Ca2+ [32]. Isolated tracheal strips and bronchiolar segments were suspended in organ baths containing Krebs' solution for isometric tension recording. Tissue responses during stepwise cooling from 37 to 5 degrees C were examined. Cooling ovine tracheal strips and bronchiolar ring segments to 20 degrees C caused a rapid contraction which decreased slowly until it reached the basal level in approximately 30 min. There is a significant inhibition of 45Ca2+ efflux at 20 degrees C to those incubated at 37 degrees C. This prompted this study whose aim was to determine the role of ion-pump and ion-carrier systems on cooling mechanisms. Inhibition of the Na+/K+ pump with ouabain (10 micrometer) evoked contraction in tracheal and bronchiolar preparations. When cooling was superimposed on this contraction the cooling-induced contractions were reduced in the bronchiolar segments. In the tracheal strips, at temperatures down to 15 degrees C ouabain converted the contractions to a relaxation, but further cooling to 10 and 5 degrees C resulted in contractions that were similar to control at 5 degrees C. Staurosporine, a protein kinase inhibitor (1 micrometer) enhanced CIC in trachea and bronchiole. Vanadate, a Ca2+-ATPase pump inhibitor (1 mm) potentiated CIC in the two preparations. Trifluoperazine and W-7, calmodulin antagonists (10 and 100 micrometer) enhanced CIC in tracheal preparations but not in the bronchiolar segments. Thapsigargin and cyclopiazonic acid (CPA), inhibitors of sarcoplasmic reticulum (SR) Ca2+-ATPase pump (1 and 10 micrometer) potentiated CIC in tracheal but not in bronchiolar preparations. Amiloride, Na+/H+ and Na+/Ca2+ exchange system inhibitor (1 mm) abolished CIC in both trachea and bronchiole. These results show a strong relationship between cooling and the activity of ion transport systems and indicate that CIC is due to inhibition of calcium removal mechanisms as a result of inhibition of these ion-pump and ion carrier systems.

Biphasic relaxant response of ovine trachealis muscle to electrical field stimulation: influence of cooling.

Electrical field stimulation of ovine trachealis muscle produced neurogenic atropine-sensitive contractions under resting conditions. However, when the tissues were precontracted with 5-hydroxytryptamine in the presence of atropine, electrical field stimulation induced a frequency-dependent tetrodotoxin-sensitive relaxation. The relaxation was biphasic, consisting of fast and slow phases. The fast component was attenuated by propranolol, indicating an action on beta-adrenoceptors. The slow phase was attenuated by capsaicin and, therefore, involved release of a peptide. These results showed that excitatory responses in ovine trachealis muscles are cholinergically mediated, while both adrenergic and peptidergic components mediate electrically induced relaxation in the trachea. We also examined the influence of lowering bath temperature to 20 degrees C on electrically evoked responses. These were significantly reduced by cooling. At 20 degrees C, under resting conditions, the time-to-peak tension was lengthened, and the amplitude of the contractile responses was significantly (p < 0.05) reduced. In the same preparation, carbachol-induced contractions were not reduced by cooling, indicating that the reduction in electrically induced contractions was probably due to a reduction in transmitter release. Cooling also abolished the fast inhibitory phase (adrenergic in nature) without significantly inhibiting the slow (non-adrenergic, non-cholinergic) component. Propranolol (1 micromol/l) and capsaicin (100 micromol/l) did not affect significantly the slow relaxation observed during cooling. It was concluded that cooling inhibited cholinergically mediated, electrically induced contractions and selectively abolished the adrenergic component of electrically induced relaxant responses.

Insulin-dependent attenuation in alpha 2-adrenoreceptor-mediated nociception in experimental diabetes.

Diabetes mellitus is associated with abnormalities in central noradrenergic dynamics, a system that appears to be involved in the regulation of nociception in both humans and experimental animals. To this end, we investigated the responsiveness of nociceptive threshold to the actions of clonidine (an alpha 2-adrenoreceptor agonist) and yohimbine (an alpha 2-adrenoreceptor antagonist) during diabetes. The induction of diabetes was achieved by the administration of streptozotocin (STZ) (55 mg/kg, intravenously). Nociceptive threshold, as indicated by the tail-flick latency of the tail immersion test, was progressively elevated as a function of the duration of diabetes. Systemic administration of clonidine and yohimbine respectively produced dose-dependent analgesic and hyperalgesic effects in control animals. Both of these phenomena were impaired in chronically diabetic animals. In contrast, insulin-treated diabetics displayed supersensitivity to clonidine's antinociceptive effect, especially at low doses. Acute hyperglycemia did not interfere with the alpha 2-agonist-mediated elevation in nociceptive threshold. Attenuation in clonidine antinociceptive effect was also observed following its intrathecal administration to diabetic animals. Overall, these data suggest that the impaired responsiveness of diabetic rats might be due to a central alpha 2-adrenoreceptor desensitization and/or biochemical defect in the postreceptor events.

Diabetes-induced suppression of IGF-1 and its receptor mRNA levels in rat superior cervical ganglia.

Insulin-like growth factor-I (IGF-I) is implicated in the development, survival and maintenance of function of sympathetic and sensory neurons. These neurons are affected at an early stage during the course of diabetes. Reverse transcriptase polymerase chain reaction (RT-PCR) based assay revealed that rat superior cervical ganglia (SCG) express mRNA transcripts for IGF-I and its receptor. Moreover, specific membrane protein binding sites for IGF-I within the SCG have also been demonstrated using competition-inhibition and affinity cross-linking techniques. An induction of diabetes with streptozotocin (STZ, 55 mg/kg, i.v.) produced a marked decrease in the SCG levels of mRNA transcripts for IGF-I and its receptor. Concentrations of circulating IGF-I and its receptor protein within the SCG were also reduced in this disease state. Insulin treatment partially prevented diabetes-related alterations in circulating IGF-I and the SCG-IGF-I system. Overall, the data described in this study may be of value in understanding the pathogenetic mechanism(s) responsible for the development of diabetic sympathetic neuropathy.

Antinociceptive action of intrathecally administered IGF-I and the expression of its receptor in rat spinal cord.

mRNA transcripts for insulin-like growth factor I (IGF-I) and its receptor are expressed in the lumbar region of the spinal cord. Accordingly, we examined the involvement of IGF-I in nociceptive transmission. An intrathecal injection of IGF-I (200-1000 ng) produced a dose-dependent elevation in nociceptive threshold as indicated by tail flick/withdrawal latency. In contrast, comparable doses of insulin had no significant effect. The time-response curve (15-75 min) revealed that the peak for IGF-I's antinociceptive effect is attained at 30 min. Our data provide evidence that the IGF-I system within the spinal cord may serve as a target for novel analgesics.

Vascular effects of some opioid receptor agonists.

Opioid peptides have been implicated in shock-associated hypotension. Our aim was to find out whether opioid agonists have direct vasodilator actions on vascular smooth muscle. The study was conducted on rat abdominal aortic rings. In rings precontracted with either norepinephrine, prostaglandin F2 alpha, or high potassium Krebs (HPK), the effects of the opioid agonists tested (morphine, U50488H, ethylketocyclazocine (EKC), and bremazocine) depended on the precontracting agent used. HPK-precontracted rings were relaxed by all agonists tested. In norepinephrine-precontracted rings, all caused contraction at low concentrations and relaxation at high concentrations except bremazocine, which caused only relaxation. In prostaglandin F2 alpha-precontracted rings, U50488H produced contraction at low concentrations and relaxation at high concentrations while EKC caused only relaxation and morphine or bremazocine caused only contraction. All relaxant responses were endothelium-independent and were antagonized by verapamil but not by a number of antagonists including naloxone. MR2266, propranolol, diphenhydramine, cimetidine, and indomethacin. They may reflect calcium channel blockade. Morphine-induced vasoconstriction was antagonized by high concentrations of of naloxone or mepyramine and may be due to release of histamine by a naloxone-sensitive mechanism. We conclude that (a) the opioid agonists tested exert direct actions on vascular smooth muscle; (b) the nature of the response depended not only on the agonist used and its concentration but also on the agent used to precontract the tissue; and (c) it is unlikely that direct actions of endogenous opioids contribute to the shock-associated hypotension because high doses were needed to elicit them.

Antinociceptive effects of localized administration of opioids compared with lidocaine.

To study possible antinociceptive effects of perineurally administered opioids, the rat infraorbital nerve block (IONB) model was employed for investigations of opioids (morphine, meperidine, buprenorphine, ethylketocyclazocine, and fentanyl) of differing receptor selectivity and physicochemical properties such as lipid solubility. Only meperidine in doses greater than 1 mg/kg produced localized analgesia, the duration of which increased dose-dependently. Naloxone failed to counteract the analgesic effects of meperidine. It is concluded that meperidine exerted its effect by a local anesthetic action and not by the activation of opioid receptors in the peripheral nerve. The local anesthetic potency of meperidine was compared with that of lidocaine in peripheral nerve blocks (IONB in rats and sciatic nerve block in guinea pigs), in central nerve blocks (epidural anesthesia in guinea pigs and spinal anesthesia in mice), and in infiltration anesthesia in guinea pigs. Time to onset of block was generally longer for meperidine. Equal amounts of the drugs produced motor blocks of similar durations except in epidural anesthesia where meperidine was clearly shorter. Sensory blocks were longer with meperidine than with lidocaine when applied in equal amounts to the infraorbital nerve and subarachnoidally. The two agents caused a similar duration of sensory block in infiltration anesthesia. Meperidine was shorter than lidocaine in epidural anesthesia. The characteristics of blocks induced by the two agents may be explained by structural differences and associated differences in physicochemical properties such as lipid solubility and pKa.

A model of chronic pain in the rat: functional correlates of alterations in the activity of opioid systems.

Intradermal inoculation of rats at the tail base with Mycobacterium butyricum led to the gradual development of an arthritic swelling of the limbs which peaked at 3 weeks and subsided thereafter. Arthritic rats displayed a loss of body weight, hypophagia, and hypodipsia in addition to a disruption of the diurnal rhythms of ingestive behavior and of core temperature. The activity of adenohypophyseal beta-endorphin-(beta-EP) secreting corticotrophs, in contrast to prolactin-(PRL) secreting lactotrophs, was increased in arthritic rats. Indeed, hypertrophy of the adrenal glands was seen. Arthritic rats also showed an elevation in spinal cord levels of immunoreactive dynorphin (DYN), an endogenous ligand of the kappa-opioid receptor. The paws and tail of arthritic rats showed lower thresholds in response to noxious pressure (hyperalgesia), higher thresholds in response to noxious heat (hypoalgesia), and no change in their response to noxious electrical stimulation. Neither naloxone nor ICI-154, 129 (a preferential delta-receptor antagonist) modified the responses of the paw or tail to pressure. However, MR 2266 (an antagonist with higher activity at kappa-receptors) decreased thresholds to pressure in arthritic, but not control, rats; that is, it potentiated the hyperalgesia. This action was stereospecific. None of the antagonists modified the response to heat. MR 2266 did not affect the response to pressure in rats with acute inflammation produced by yeast. Thus, the potentiation of pressure hyperalgesia by MR 2266 in chronic arthritic rats is highly selective. Arthritic rats showed a reduced response to the analgesic effect of a kappa-agonist (U-50,488H), whereas the response to a mu-agonist (morphine) was enhanced. These effects were specific to nociception in that their influence upon endocrine secretion (PRL and beta-EP) was otherwise changed. The secretion of beta-EP and PRL was stimulated by both morphine and U-50,488H, and the influence of U-50,488H upon the release of beta-EP (from the adenohypophysis) was enhanced in arthritic rats. It is suggested that polyarthritis is a complex condition entailing many changes, both behavioral and endocrinological. Further, arthritic rats cannot simply be described as "hyperalgesic": of critical importance is the nature of the nociceptive stimulus applied. The parallel alterations in spinal cord pools of DYN and kappa-receptors (see also Millan et al., 1986) and the changes in the influence on nociception of kappa-agonists and kappa-antagonists suggest an increased activity of spinal DYN. Thus, spinal kappa-receptors may play a role in the modulation of nociception under chronic pain.(ABSTRACT TRUNCATED AT 400 WORDS)

A model of chronic pain in the rat: response of multiple opioid systems to adjuvant-induced arthritis.

Chronic arthritic pain was induced by intradermally inoculating rats at the tail-base with Mycobacterium butyricum, which results in swelling, inflammation, and hyperalgesia of the joints. These symptoms peak at 3 weeks after inoculation and disappear by 10 weeks. The following changes were seen at 3 weeks. Immunoreactive dynorphin (ir-Dyn) and ir-alpha-neo-endorphin (alpha-NE) manifested comparable patterns of change. Their levels were increased in the anterior, but not neurointermediate, pituitary. The thalamus showed a rise in ir-Dyn and ir-alpha-NE, but no alterations were seen in other brain regions. In each case, cervical, thoracic, and lumbosacral sections of the spinal cord showed a rise in ir-Dyn and ir-alpha-NE: This was most pronounced in the lumbosacral region, where the magnitude of these shifts correlated with the intensity of arthritic symptoms. In addition, a moderate elevation in ir-methionine-enkephalin (ME) was seen in lumbosacral spinal cord. In brain, ir was not changed. The level of ir-beta-endorphin (beta-EP) was elevated both in the plasma and the anterior, but not the neurointermediate, pituitary. In addition, the content of messenger RNA encoding the beta-EP precursor, proopiomelanocortin (POMC), was enhanced in the anterior lobe. Thus, there was a selective activation of synthesis of beta-EP in, and its secretion from, the anterior lobe. In no brain tissue did levels of ir-beta-EP change. At 10 weeks postinoculation, the above changes were no longer apparent, indicating their reversibility.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperalgesia produced by intrathecal opioid antagonists depends on receptor selectivity and noxious stimulus.

Opioid antagonists selective for delta-, kappa- and mu-receptor subtypes were administered intrathecally in rats prior to determination of response thresholds to noxious heat, pressure and chemical visceral stimulation. All antagonists induced hyperalgesia differentially with two or more stimuli but delta- and mu-blockade failed to alter writhing activity. Thus, the extent of involvement of an opioid receptor subtype in antinociception depends on the type of noxious stimulation.

Spinal cord dynorphin may modulate nociception via a kappa-opioid receptor in chronic arthritic rats.

Inoculation of rats with Mycobacterium butyricum produced an arthritis of the limbs which revealed an enhanced sensitivity to noxious mechanical pressure (hyperalgesia). Arthritic rats displayed a pronounced rise in immunoreactive dynorphin in lumbo-sacral spinal cord which correlated both with the intensity and time-course of this hyperalgesia. MR-2266, a relatively preferential antagonist at the chi-opioid receptor (at which dynorphin is considered to act) potentiated this hyperalgesia. In contrast, MR 2267 (its inactive stereo-isomer) was ineffective. Further, naloxone (a weak chi-antagonist), and ICI 154,129 (a preferential delta-antagonist) were, in each case, inactive. The data demonstrate a pronounced response of spinal dynorphin to chronic arthritic pain in the rat. In addition, they raise the possibility of a function of spinal DYN, via a chi-receptor, in the modulation of chronic arthritic pain.

Chronic pain in the rat: selective alterations in CNS and pituitary pools of dynorphin as compared to vasopressin.

Inoculation of rats at the tail-base with Mycobacterium led to arthritic swelling and inflammation of all four limbs. Immunoreactive (ir)-dynorphin (DYN) increased in anterior but not neurointermediate pituitary. In the brain, only thalamus showed a rise and, in spinal cord, a large elevation was seen. Ir-vasopressin (VP) was not affected in these tissues but increased in midbrain. These effects might reflect a role of DYN in the control of chronic pain. In addition, they support a differential modulation of DYN as compared to VP extrinsic to the hypothalamic-neurohypophyseal axis.

Effects of naloxone and Mr 1452 on stress-induced changes in nociception of different stimuli in rats.

The effects of naloxone and Mr 1452 on nociceptive responding to heat and pressure following restraint stress were examined. Thresholds for heat and pressure were determined using standard tail immersion and paw pressure tests. Restraint produced significant analgesia to heat but hyperalgesia to pressure. Naloxone reduced this heat analgesia but had no effect on stress-induced hyperalgesia to pressure. Mr 1452 also attenuated the heat analgesia but in contrast to naloxone it potentiated the hyperalgesia to pressure. These results suggest a differential involvement of mu- and k-opioid systems in the mediation of stress-induced changes in nociception.