Central Endogenous Opioid System Research Articles

Attenuation of immobilization stress-induced hypertension by temperature-controllable warm needle acupuncture in rats and the peripheral neural mechanisms.

We and others have shown that electrical stimulation of the PC-6 acupoint over the wrist relieves hypertension by stimulating afferent sensory nerve fibers and activating the central endogenous opioid system. Warm needle acupuncture has long been utilized to treat various diseases in clinics. Here, we developed a temperature-controllable warm needle acupuncture instrument (WAI) and investigated the peripheral mechanism underlying the effect of warm needle acupuncture at PC-6 on hypertension in a rat model of immobilization stress-induced hypertension. Stimulation with our newly developed WAI and traditional warm needle acupuncture attenuated hypertension development. Such effects were reproduced by capsaicin (a TRPV1 agonist) injection into PC-6 or WAI stimulation at 48°C. In contrast, PC-6 pretreatment with the TRPV1 antagonist capsazepine blocked the antihypertensive effect of WAI stimulation at PC-6. WAI stimulation at PC-6 increased the number of dorsal root ganglia double-stained with TRPV1 and CGRP. QX-314 and capsaicin perineural injection into the median nerve for chemical ablation of small afferent nerve fibers (C-fibers) prevented the antihypertensive effect of WAI stimulation at PC-6. Additionally, PC-6 pretreatment with RTX ablated the antihypertensive effect of WAI stimulation. These findings suggest that warm needle acupuncture at PC-6 activates C-fiber of median nerve and the peripheral TRPV1 receptors to attenuate the development of immobilization stress-induced hypertension in rats.

Role of central versus peripheral opioid system in antinociceptive and anti-inflammatory effect of botulinum toxin type A in trigeminal region.

Although botulinum toxin type A (BT-A) is approved for chronic migraine treatment, its site and mechanism of action are still elusive. Recently our group discovered that suppression of CGRP release from dural nerve endings might account for antimigraine action of pericranially injected BT-A. We demonstrated that central antinociceptive effect of BT-A in sciatic region involves endogenous opioid system as well. Here we investigated possible interaction of BT-A with endogenous opioid system within the trigeminal region. In orofacial formalin test we investigated the influence of centrally acting opioid antagonist naltrexone (2mg/kg, s.c.) versus peripherally acting methylnaltrexone (2mg/kg, s.c.) on BT-A's (5 U/kg, s.c. into whisker pad) or morphine's (6mg/kg, s.c.) antinociceptive effect and the effect on dural neurogenic inflammation (DNI). DNI was assessed by Evans blue-plasma protein extravasation. Naltrexone abolished the effect of BT-A on pain and dural plasma protein extravasation, whereas peripherally acting methylnaltrexone did not change either BT-A's effect on pain or its effect on dural extravasation. Naltrexone abolished the antinociceptive and anti-inflammatory effects of morphine, as well. However, methylnaltrexone decreased the antinociceptive effect of morphine only partially in the second phase of the test and had no significant effect on morphine-mediated reduction in DNI. Morphine acts on pain in trigeminal region both peripherally and centrally, whereas the effect on dural plasma protein extravasation seems to be only centrally mediated. However, the interaction of BT-A with endogenous opioid system, with consequent inhibition of nociceptive transmission as well as the DNI, occurs primarily centrally. Botulinum toxin type A (BT-A)'s axonal transport and potential transcytosis suggest that its antinociceptive effect might involve diverse neurotransmitters at different sites of trigeminal system. Here we discovered that the reduction in pain and accompanying DNI involves the interaction of BT-A with central endogenous opioid system (probably at the level of trigeminal nucleus caudalis).

P 4. Cerebral blood flow modulation by transcutaneous cranial electrical stimulation with Limoge’s current

Objectives TCES delivers a high-frequency (166 kHz) pulsed biphasic balanced current with a pulse repetition frequency of 100 Hz with 40% duty cycle through a negative electrode and two positive electrodes over the skull. TCES has a proven ability to potentiate anesthesia and analgesia, although the physiological mechanisms of this effect remain unclear. We hypothesized that the mechanism is a modulation of CBF in the central endogenous opioid system. This study aimed at determining the effects of TCES on CBF to elucidate its physiological mechanism. Methods Thirty-six healthy volunteers were randomly assigned to active or placebo TCES, and all assessments were double blind. TCES was performed using the Anesthelec™ device. In the stimulated group, an active cable was used, and in the control group (sham), the cable was inactive. CBF was measured by XeCT™ before and after two hours of TCES. Results Globally, CBF was unchanged by TCES. However, locally, TCES induced a significant CBF decrease in the brainstem and thalamus, which are structures involved in pain and anxiety (TCES and control CBF decrease were 18.5 and 11.9 mL/100 g brain tissue/min, respectively). Conclusion TCES can modulate local CBF but it has no effect on overall CBF. [Clinical Trials.gov number: NCT00273663].

Cerebral blood flow modulation by transcutaneous cranial electrical stimulation with Limoge's current

Transcutaneous cranial electrical stimulation (TCES) delivers a high-frequency (166 kHz) pulsed biphasic balanced current with a pulse repetition frequency of 100 Hz with 40% duty cycle through a negative electrode and two positive electrodes over the skull. TCES has a proven ability to potentiate anesthesia and analgesia, although the physiological mechanisms of this effect remain unclear. We hypothesized that the mechanism is a modulation of CBF in the central endogenous opioid system. This study aimed at determining the effects of TCES on CBF to elucidate its physiological mechanism. Thirty-six healthy volunteers were randomly assigned to active or placebo TCES, and all assessments were double blind. TCES was performed using the Anesthelec™ device. In the stimulated group, an active cable was used, and in the control group (sham), the cable was inactive. CBF was measured by XeCT™ before and after two hours of TCES. Globally, CBF was unchanged by TCES. However, locally, TCES induced a significant CBF decrease in the brainstem and thalamus, which are structures involved in pain and anxiety (TCES and control CBF decrease were 18.5 and 11.9 mL/100g brain tissue/min, respectively). TCES can modulate local CBF but it has no effect on overall CBF. [Clinical Trials. gov number: NCT00273663].

Black cohosh has central opioid activity in postmenopausal women

To test whether black cohosh (BC) exhibits an action on the central endogenous opioid system in postmenopausal women. This was a mechanistic study conducted in the same individuals of luteinizing hormone pulsatility with a saline/naloxone challenge (n = 6) and positron emission tomography with [C]carfentanil, a selective micro-opioid receptor radioligand (n = 5), before and after 12 weeks of unblinded treatment with a popular BC daily supplement. BC treatment for 12 weeks at a standard dose (Remifemin, 40 mg/day) had no effect on spontaneous luteinizing hormone pulsatility or estrogen concentrations. With naloxone blockade, there was an unexpected suppression of mean luteinizing hormone pulse frequency (saline vs naloxone = 9.0 +/- 0.6 vs 6.0 +/- 0.7 pulses/16 h; P = 0.056), especially during sleep when the mean interpulse interval was prolonged by approximately 90 minutes (saline night interpulse interval = 103 +/- 9 min vs naloxone night interpulse interval = 191 +/- 31 min, P = 0.03). There were significant increases in mu-opioid receptor binding potential in the posterior and subgenual cingulate, temporal and orbitofrontal cortex, thalamus, and nucleus accumbens ranging from 10% to 61% across brain regions involved in emotional and cognitive function. In contrast, binding potential reductions of lesser magnitude were observed in regions known to be involved in the placebo response (anterior cingulate and anterior insular cortex). Using two different challenge paradigms for the examination of central opioid function, a neuropharmacologic action of BC treatment was demonstrated in postmenopausal women.

The role of central endogenous opioid system in the regulation of gastric mucosal integrity

The role of central endogenous opioid system in the regulation of gastric mucosal integrity

Naltrexone affects cocaine self-administration in naı̈ve rats through the ventral tegmental area rather than dopaminergic target regions

Behavioural studies have shown an involvement of central endogenous opioid systems in experimental cocaine addiction. Seeking to further localize the attenuating effect of opioid blockade on the reinforcing effects of cocaine, naltrexone was administered locally to different regions of the mesocorticolimbic system, which are thought to be critically involved in cocaine self-administration behaviour. Both cell body and nerve terminal regions of this system were targeted. Using a model for the initiation of cocaine self-administration behaviour, no effect of naltrexone was found in caudate, amygdaloid or accumbens nuclei, nor in the medial prefrontal cortex. However, blockade of endogenous opioid receptors in the ventral tegmental area region attenuated cocaine self-administration. With the initiation model, this finding reflects an attenuating effect on the reinforcing effects of cocaine. The attenuation of self-administration was dependent on the naltrexone dose. The present findings suggest that endogenous opioid systems in the ventral tegmental area modulate the reinforcing efficacy of cocaine.

Interleukin-6 is differently modulated by central opioid receptor subtypes.

The central endogenous opioid system is involved in the modulation of interleukin (IL)-6, an inflammatory cytokine that plays a major role in the acute phase response. The present study evaluates whether specific opioid receptor subtypes are selectively involved in this immunomodulatory action. IL-1 beta was administered either intracerebroventricularly or intraperitoneally at the dose of 400 ng to rats pretreated with the mu-antagonist beta-funaltrexamine, the delta-antagonist naltrindole, or the kappa-antagonist nor-binaltorphimine, each at the doses of 1, 10, and 100 micrograms/rat intracerebroventricularly. Serum IL-6 levels were measured 2 h later. The results show that mu-receptor blockade increases, whereas delta-receptor blockade decreases IL-6 induction, suggesting that the fine tuning exerted by opioids on the immune system may be achieved through a balance of opposing effects. Moreover the three antagonists affect IL-6 induction by central and peripheral IL-1 beta with a similar pattern, indicating that the brain endogenous opioid system plays a general role in the regulation of this cytokine.

Endogenous opioid system modulation in anginal pain: Demonstration of its central activity

Plasma β-endorphin levels provide controversial results on the role of endogenous opioid system in modulation of anginal pain. As an alternative, the action of plasmatic luteinizing hormone after administration of naloxone was investigated: naloxone blocks the tonic endogenous opioid system inhibition of gonadotropin release; thus, the level of luteinizing hormone after naloxone administration is an index of central endogenous opioid system activity. Twenty patients with coronary artery disease and positive results of stress tests were selected: 10 had angina (group I) and 10 did not (group II). Ten healthy subjects were also studied as a control group (group III). In all patients basal plasma β-endorphin levels, basal luteinizing hormone plasma levels (every 15 minutes for 1 hour) and luteinizing hormone plasma levels after administration of 0.1 mg/kg naloxone over 4 minutes (every 15 minutes for 2 hours) were determined. In 15 patients the test was performed after luteinizing hormone releasing hormone was given. The integral concentration time of luteinizing hormone plasma level during baseline (LHiB) and after administration of naloxone (LHiN) or luteinizing hormone releasing hormone (LHiRH), the ratio (LHiN:LHiB and LHiRH:LHiB) and the differences (LHiN-LHiB and LHiRH − LHiB) between the postinfusion period and baseline were calculated. No difference was found in β-endorphin plasma levels and luteinizing hormone response after luteinizing hormone releasing hormone infusion. On the contrary, after naloxone administration, group II showed significantly higher responses (LHiN − LHiB, 2413 ± 380 mlU/ml; LHiN:LHiB, 5 ± 0.4) with respect to group I (LHiN − LHiB, 1150 ± 304 mlU/ml; p < 0.001; LHiN:LHiB, 2.7 ± 0.6; p < 0.001) and to group III (LHiN − LHiB, 1048 ± 279 mlU/ml; p < 0.001; LHiN:LHiB, 2.6 ± 0.4, p < 0.001). In comparison with β-endorphin levels, luteinizing hormone response to naloxone provides a better discrimination between patients with symptoms and those without symptoms, which demonstrates the role of the endogenous opioid system in modulating anginal pain.

Correlation between cerebrospinal fluid phenylalanine and β-endorphin in patients with phenylketonuria

Previous animal and human studies have suggested an analgesic effect of phenylalanine involving endogenous opioid peptides. Phenylalanine was measured by a HPLC method with electrochemical detection and β-endorphin by a specific radioimmunoassay in 14 lumbar cerebrospinal fluid samples from 13 patients with phenylketonuria. Cerebrospinal fluid β-endorphin was also determined in 6 age-matched control subjects. We found a trend towards a higher β-endorphin level in phenylketonuria (median 26.0 pM, range 13.0–37.8) than in the control subjects (20.6 pM, 12.7–28.0), P = 0.13. Cerebrospinal fluid concentrations of phenylalanine and β-endorphin were significantly correlated ( r = 0.68, P = 0.008). The results support the hypothesis that phenylalanine modifies the central endogenous opioid system.

Seasonal changes in methionine-enkephalin immunoreactivity in the brain of a hibernator, Spermophilus columbianus

To identify the actual location of central endogenous opioid systems which may be involved in regulating the hyberbation cycle, differences in the pattern of central methionine-enkephalin (Met-EK) immunoreactivity were compared between hibernating (body temperature, T b = 7 °C) and non-hibernating ( T b = 37 °C) Columbia ground using the peroxidase-antiperoxidase technique. In non-hibernating animals, Met-EK-immunoreactive perikya were observed in telencephalic (putamen, caudate,, nucleus, medial septum-diagonal band complex, amygdala) and diencephalic (periventricular hypothalamic nucleus, lateral hypothalamic area) regions; whereas immunoreactive fibers were found in the lateral septum, stria terminalis nucleus, various hypothalamic areas, arcuate nucleus, median eminence, thalamic intralaminar, periventricular nucleus and lateral habenular nucleus. Compared to the non-hiberbnating animal, a marked increase in the number of Met-EK-immunoreactive fibers was found in the lateral septal nucleus, the periventricular nucleus, the intralaminar thalamus and the paraventricular hypothalamus of hibernating ground squirrels. Since these changes in immunoreactivity were not observed in the artificially induced hypothermic ground squirrels ( T b = 7 °C), it is unlikely that the dissimilarity in immunoreactivity between animals from different hibernating phases is due to differences in their T b. In combination with our previous studies, these results tend to suggest that hibernation maybe be brought about an increase in endogenous opioid activity, especially in the lateral septal region.

Stress- and morphine-induced elevations of plasma and tissue cholesterol in mice: Reversal by naltrexone

Our earlier studies indicated that stress-induced facilitation of gallstone formation could be prevented by the opiate antagonist naltrexone. In view of the possible link between gallstone formation and atherosclerosis, the present study examined the possibility that endogenous opioids might also mediate stress-induced hypercholesterolemia. A 28-day immobilization stress schedule was used to induce increases in plasma, aortic and liver cholesterol of mice maintained on a high cholesterol diet. These stress-induced increases in plasma, hepatic and aortic cholesterol were reversed by pretrcatment with the opiate antagonist, naltrexone (1 mg/kg). Exposure of mice to morphine (0.1% in the drinking water for 28 days) resulted in elevations of plasma, liver, and aortic cholesterol levels, similar to those observed following immobilization. In contrast, chronic exposure to the peripherally restricted opiate agonist, loperamide (0.1% in the drinking water for 28 days), was ineffective. The antagonism by naltrexone and duplication by morphine but not loperamide suggest that stress-induced hypercholesterolemia may require the activation of central endogenous opioid systems.

Irradiation exposure modulates central opioid functions

Exposure to low doses of gamma irradiation results in the modification of both the antinociceptive properties of morphine and the severity of naloxone-precipitated withdrawal in morphine-dependent rats. To better define the interactions between gamma irradiation and these opiate-mediated phenomena, dose-response studies were undertaken of the effect of irradiation on morphine-induced antinociception, and on the naloxone-precipitated withdrawal syndrome of morphine-dependent rats. In addition, electrophysiologic studies were conducted in rats after irradiation exposure and morphine treatment correlating with the behavioral studies. The observations obtained demonstrated that the antinociceptive effects of morphine as well as naloxone-precipitated withdrawal were modified in a dose-dependent manner by irradiation exposure. In addition, irradiation-induced changes in the evoked responses obtained from four different brain regions demonstrated transient alterations in both baseline and morphine-treated responses that may reflect the alterations observed in the behavioral paradigms. These results suggest that the effects of irradiation on opiate activities resulted from physiologic alterations of central endogenous opioid systems due to alterations manifested within peripheral targets.