Differential effect of morphine on trigeminal nucleus versus reticular aversive stimulation: independence of negative effects from stimulation parameters.

Electrodes were implanted in mesencephalic, pontine, and bulbar reticular formation, and in spinal trigeminal nucleus and tract of rats. Central and peripheral aversive response thresholds were studied under normal conditions and with morphine. Peripherally elicited aversive reactions were assessed with tail-flick, hot-plate, and footshock responses. Centrally elicited aversive reaction thresholds were in all cases based on unconditioned behavioral distress signs (non-stereotyped, escape-like movements, vocalization, freezing, excretion, etc.) and confirmed in some cases with avoidance learning. Morphine (10 mg/kg) elevated the unconditioned aversive reaction threshold for brain stimulation in the trigeminal complex and for peripheral aversive stimulation, but failed to affect the thresholds for reticular brain stimulation. The failure to affect reticular thresholds was independent of stimulation frequency. Thresholds for 5 and 200 Hz sinusoidal stimulation were both unaffected as were previously reported thresholds with 333 Hz pulsatile stimulation. Trigeminal nucleus and tract stimulation were affected in similar degrees. The data were discussed as supporting descending inhibitory models of opiate analgesia.     

A practical approach to determine cutoff concentrations for opiate testing with simultaneous detection of codeine, morphine, and 6-acetylmorphine in urine

BACKGROUND: Both the Department of Defense (DoD) and the Department of Health and Human Services (DHHS) currently require two confirmation tests to verify use of heroin, one test for total morphine and a separate test for 6-acetylmorphine (6-AM). Our aim was to determine appropriate free-codeine, free-morphine, and 6-AM cutoff concentrations that could be substituted for total-morphine, total-codeine, and 6-AM cutoff concentrations and to develop a less labor-intensive method for measuring codeine, morphine, and 6-AM. METHODS: Urine samples containing opiates were extracted, derivatized, and analyzed using gas chromatography-mass spectrometry with selective ion monitoring. RESULTS: The limits of detection for codeine, morphine, and 6-AM were 6, 5, and 0.5 microg/L, respectively. Recoveries were >90%. Quantification was linear over the concentration range of 6-1000 microg/L for codeine, 5-5000 microg/L for morphine, and 0.5-800 microg/L for 6-AM. Cutoff concentrations for confirmation of opiates were 100, 100, and 10 microg/L for free codeine, free morphine, and 6-AM. CONCLUSION: The proposed cutoff concentrations for free morphine and 6-AM provide better detection windows for morphine and heroin use than the cutoff concentrations for total morphine and 6-AM used at present. Detection of free codeine, instead of total codeine, simplifies interpretation of codeine use. The single-extraction method enables simultaneous, less labor-intensive analysis of morphine, codeine, and 6-AM.Copyright 1999 American Association for Clinical Chemistry     

The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats

A method for assessing pain and analgesia in rats and cats is described. The procedure involves subcutaneous injection of dilute formalin into the forepaw, after which the animal's responses are rated according to objective behavioral criteria. The formalin test is a statistically valid technique which has two advantages over other pain tests: (1) little or no restraint is necessary, permitting unhindered observation of the complete range of behavioral responses; and (2) the pain stimulus is continuous rather than transient, thus bearing greater resemblance to most clinical pain. The analgesic effects of morphine, meperidine, and stimulation of the periaqueductal grey matter are evaluated using this test.     

Dissociation of rewarding,anti‐aversive and anti‐nociceptive effects of different classes of anti‐nociceptives in the rat

It was previously shown that morphine more potently reduces the affective as compared to the sensory component of nociception, and this effect is independent of morphine's rewarding properties. Here we investigated whether this finding can be generalized to other classes of anti‐nociceptive drugs. The effect of oxycodone (0–10 mg/kg, i.p.), tramadol (0–10 mg/kg, i.p.), ibuprofen (0–300 mg/kg, i.p.) and pregabalin (0–31.6 mg/kg, i.p.) on negative affect and mechanical hypersensitivity accompanying carrageenan‐induced (0.5% intraplantar) inflammatory nociception was assessed using conditioned place aversion (CPA) and Randall Selitto paw pressure test, respectively. The rewarding effect of these drugs was assessed using conditioned place preference (CPP). All four anti‐nociceptive drugs dose‐dependently reduced carrageenan‐induced CPA and mechanical hypersensitivity. Furthermore all drugs induced CPP, except for ibuprofen. Similar to morphine, oxycodone and tramadol showed a large dissociation of anti‐aversive versus anti‐nociceptive potency, i.e. 10 times more potent against the affective versus the sensory component of nociception. Oxycodone and tramadol were 30 and 10 times more potent to produce CPP in animals under normal versus painful conditions. Ibuprofen and pregabalin also showed a dissociation of anti‐aversive and anti‐nociceptive potency, but less pronounced (i.e. three times more potent against the affective component). However, pregabalin showed no dissociation between rewarding potency under normal versus painful conditions. Taken together, these data suggest that the dissociation of rewarding potency in animals under normal versus painful conditions is limited to drugs with an opioid mechanism of action, while the dissociation of anti‐aversive and anti‐nociceptive potency applies to anti‐nociceptive drugs with different mechanisms of action.     

Comparative analgesic effects of H-wave therapy and transcutaneous electrical nerve stimulation on pain threshold in humans.

OBJECTIVE: To assess the comparative analgesic efficacy of H-wave therapy (HWT) and transcutaneous electrical nerve stimulation (TENS) using a mechanical model of pain threshold measurement. STUDY DESIGN: Forty-eight healthy human volunteers (24 women, 24 men) were recruited and randomly assigned into one of six experimental groups; control, HWT (placebo, 2Hz, or 60Hz), or TENS (placebo or 110Hz). For each subject, mechanical pain threshold (MPT) measurements were recorded at three standardized recording points marked on the dorsal web space of the dominant hand. Two MPT measurements were recorded at each point at the following time intervals: before treatment was initiated (baseline), after each of three consecutive 10-minute periods of stimulation (HWT or TENS), and at four intervals within 30 minutes after stimulation. In the control and placebo groups MPT measurements were recorded at similar time intervals. RESULTS: Difference scores, calculated from patients' baseline values, were analyzed by ANOVA for each of the three recording points. Although results showed a significant increase in MPT levels in all three stimulation groups when compared with their relative placebo (indicating a hypoalgesic effect), no differences were observed between the different modalities or HWT frequencies. Significant hypoalgesia continued for 5 minutes after stimulation. CONCLUSION: The findings showed that HWT and TENS provided localized hypoalgesia during stimulation and for up to 5 minutes after it. No frequency- or modality-specific effects were observed between the groups.     

Deep brain light stimulation effects on glutamate and dopamine concentration

Compared to deep brain electrical stimulation, which has been applied to treating pathological brain diseases, little work has been done on the effect of deep brain light stimulation. A fiber-coupled laser stimulator at 840 nm wavelength and 130 Hz pulse repetition rate is developed in this work for deep brain light stimulation in a rat model. Concentration changes in glutamate and dopamine in the striatum are observed using a microdialysis probe when the subthalamic nucleus (STN) is stimulated at various optical power levels. Experimental results show that light stimulation causes the concentration of glutamate to decrease while that of dopamine is increased. This suggests that deep brain light stimulation of the STN is a promising therapeutic strategy for dopamine-related diseases such as Parkinson’s disease. The stimulator developed for this work is useful for deep brain light stimulation in biomedical research.OCIS codes: (170.5180) Photodynamic therapy, (170.3660) Light propagation in tissues, (170.3890) Medical optics instrumentation, (170.1420) Biology, (170.1610) Clinical applications, (170.0170) Medical optics and biotechnology     

Rapid elevation of plasma interleukin-6 by morphine is dependent on autonomic stimulation of adrenal gland.

Several studies have demonstrated that opioids regulate a number of immune cell functions either through direct mechanisms or through the modulation of central nervous system outputs. It has been previously shown that morphine increases serum interleukin-6 (IL-6) levels; however, the mechanism by which this effect is produced is unknown. In the present study, experiments were designed to address the potential role of central opioid receptors, peripheral autonomic ganglia, and activation of the adrenals in the elevation of plasma IL-6 after morphine administration. A rapid and significant (2-fold) increase in plasma IL-6 was observed after morphine administration (10 mg/kg s.c.) to rats. This effect of morphine peaked within 30 min and remained elevated for at least 2 h. Central microinjection of morphine (10 microg/2 microl i.c.v.) mimicked the effects of peripherally administered morphine and was completely blocked by naltrexone (10 mg/kg s.c.) pretreatment. Pretreatment with a ganglionic blocker, chlorisondamine (0.5 mg/kg i.p.), also blocked the elevation of IL-6 by morphine, suggesting a role of the autonomic nervous system. In adrenalectomized animals, morphine administration did not increase IL-6 levels, whereas in adrenal demedullated animals, the effect of morphine remained intact. Thus, the adrenal cortex may be a potential source of IL-6, because IL-6 mRNA has been localized in the adrenal gland. Collectively, these data suggest a unique mechanism by which stimulation of central opioid receptors results in the elevation of plasma IL-6 through autonomic activation specifically of the adrenal cortex.     

Selective encoding and retrieval of affective words during exposure to aversive stimulation.

It has been demonstrated that memory for pain plays an important role in medical practice. Since affect is an integral component of the pain experience, it is possible that pain may produce effects on memory that parallel those engendered by emotion. This investigation examined whether acute pain selectively influenced the encoding and retrieval of affective words. The results indicated that the experience of pain significantly decreased the encoding of positive words and significantly increased the retrieval of negative words previously seen, regardless of whether they were accompanied by a painful experience. Thus, pain interferes with memory of positive events by disrupting their encoding and facilitates the memory of negative events through selective retrieval of those events.     

Heroin acts on different opioid receptors than morphine in Swiss Webster and ICR mice to produce antinociception.

The opioid receptor types involved in supraspinal and spinal heroin-induced analgesia in Swiss Webster and ICR mice were determined by intracerebroventricular (i.c.v.) and intrathecal (i.t.) administration of opioid agonists and antagonists. Also, comparisons were made with morphine. Antinociception was measured by changes in tail-flick latency. In Swiss Webster mice, i.c.v. heroin like [D-Pen2-D-Pen5]enkephalin, a delta receptor opioid agonist, activated supraspinal delta opioid receptors as evidenced by inhibition of analgesia by coadministration of naltrindole, a delta receptor antagonist. Lack of effect of i.t. yohimbine and methysergide vs. i.c.v. heroin indicated that spinal descending noradrenergic and serotonergic systems were not involved. Heroin and [D-Pen2-D-Pen5]enkephalin were also matched in producing additive interactions with i.t. opioids. Also, i.c.v. heroin like [D-Pen2-D-Pen5]enkephalin did not activate a dynorphin-mediated antianalgesic system. In ICR mice, i.c.v. heroin receptor selectivity matched that of i.c.v. Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5, a selective mu receptor opioid agonist. Analgesia was inhibited by pretreatment with i.c.v. beta-funaltrexamine, a nonequilibrium mu receptor antagonist. Intrathecal administration of methysergide inhibited i.c.v. heroin-induced analgesia whereas i.t. yohimbine had no effect, which indicated that a descending serotonergic system but not a noradrenergic system was involved. Low doses of i.t. naloxone and nor-binaltorphimine increased the analgesic effect. This effect was consistent with activation of an antianalgesic system by i.c.v. heroin, which was mediated by dynorphin A in the spinal cord. Desensitization of the antianalgesic system also resulted in increased analgesia. In both Swiss Webster and ICR mice, i.t. heroin-induced analgesia involved spinal mu receptors like those stimulated by Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5. Analgesia was inhibited by i.t. naloxone. In both strains, i.t. heroin, like i.t. Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5, produced an additive interaction with i.t. clonidine. In conclusion, the supraspinal receptors activated by heroin are different between Swiss Webster and ICR mice. In both strains, the receptor selectivities assigned to heroin did not match those for morphine. Heroin did not act by being biotransformed to morphine.     

Immunologic effects of morphine in rodents, rabbits, monkeys, and cats.

The effects of prolonged morphine administration on immunologic reactivity against morphine was studied in a number of animal species: rabbit, monkey, guinea pig, rat, and cat. Some evidence for increased serum binding of 14C-labeled morphine was noted after morphine treatment in all test species, with the rabbit the best responder and the cat showing little or no response. In addition to measurements on serum binding of 14C-labeled morphine, other methods (measurement of serum binding of 14C-labeled codeine and methadone, competitive inhibition tests, radial immunodiffusion, and passive hemagglutination) were used for one or more of the species. Overall, results with these test methods have shown that prolonged morphine administration can result in immunologic responsiveness to morphine in animals.     

The effects of proprioceptive stimulation on cognitive processes in patients after traumatic brain injury.

OBJECTIVE: To investigate the hypothesis that proprioceptive stimulation may be effective in the treatment of brain injury, using neurophysiologic and neuropsychologic measures. DESIGN: Cohort analytic study. SETTING: Patients recovering from traumatic brain injury (TBI) in a neurologic rehabilitation hospital were examined. PARTICIPANTS: Eleven patients with TBI (Glasgow Coma Scale score > 3) and 11 healthy control subjects matched for age and education. INTERVENTIONS: Subjects were examined with the event-related potential (ERP) technique during a computerized choice-reaction-time task, in which they had to discriminate between even and odd digits. There were experimental runs with and without vibratory stimuli applied to the left forearm serving as proprioceptive stimulation. In addition, ERPs were recorded to vibratory stimuli without any additional task. MAIN OUTCOME MEASURES: Outcome measures included latencies and amplitudes of the P300 ERP component and of the late negative component. RESULTS: In the passive vibration condition, both groups showed the same ERP distribution. In the choice-reaction-time task, latencies and amplitudes of the P300 differed between the 2 groups. The patient group showed longer P300 latencies, which were shortened by vibratory stimuli. In contrast, the control subjects were not affected by vibratory stimuli. CONCLUSION: Our findings support the hypothesis that pathologic cognitive processes after TBI can be improved by proprioceptive stimulation. Muscle vibration has positive effects on pathologically slowed cognitive processes but not in healthy subjects.     

Effects of pain-attenuating brain stimulation and morphine on electrical activity in the raphe nuclei of the awake rat

Evoked potential and multiple unit responses to noxious shock and pinch as well as to innocuous air puffs were recorded in the dorsal raphe, median raphe and raphe magnus nuclei of awake rats. Concurrent measurements of various behavioral responses to noxious stimuli were also made. Electrical stimulation of midbrain central gray and of medial thalamus, as well as systemic administration of morphine, greatly diminished all behavioral and electrophysiological responses to noxious stimuli without reliably affecting responses to air puffs. At the same time that brain stimulation and morphine attenuated nociceptive responses, a significant elevation was seen in the spontaneous multiple unit activity of these brain areas, particularly nucleus raphe magnus. In another group of animals, a comparison was made of the analgesic effectiveness of stimulation sites in the bulbar raphe (including raphe magnus) and sites dorsal or lateral to this region. More consistently potent effects were obtained from the raphe placements. These findings point to the importance of the bulbar raphe in mechanisms of analgesia. It is suggested that brain stem stimulation and morphine administration activate descending controls of raphe origin which selectively inhibit nociceptive elements in the spinal cord.     

Correlation between locomotor stimulation and the electrophysiological effects of low doses of morphine on substantia nigra dopamine neurons. I. Acute drug administration

Parallel experiments were done to determine whether the behavioral effects of low doses of morphine correlated with changes in the electrophysiological activity of two subpopulations of mesencephalic dopamine neurons in rats. Acute administration of morphine sulfate (0.01 or 0.20 mg/kg i.v.) produced a naloxone antagonizable increase in locomotion and a corresponding increase in the discharge rates of Type A dopamine neurons. Morphine sulfate led to a relatively long-latency (120-200 sec) loss of spontaneous discharge activity in the majority of Type B dopamine neurons and this was blocked by a high dose of naloxone (5.0 mg/kg). Naloxone (0.10 or 5.0 mg/kg i.v.), combined with morphine, led to a paradoxical behavioral suppression. These data suggest that morphine produces opposite effects on two functionally distinct subtypes of neurons in the substantia nigra pars compacta and that behavioral output may reflect an interaction between these changes in discharge activity in mesencephalic dopamine pathways.     

Altering gender role expectations: effects on pain tolerance, pain threshold, and pain ratings.

The literature demonstrating sex differences in pain is sizable. Most explanations for these differences have focused on biologic mechanisms, and only a few studies have examined social learning. The purpose of this study was to examine the contribution of gender-role stereotypes to sex differences in pain. This study used experimental manipulation of gender-role expectations for men and women. One hundred twenty students participated in the cold pressor task. Before the pain task, participants were given 1 of 3 instructional sets: no expectation, 30-second performance expectation, or a 90-second performance expectation. Pain ratings, threshold, and tolerance were recorded. Significant sex differences in the "no expectation" condition for pain tolerance (t = 2.32, df = 38, P <.05) and post-cold pressor pain ratings (t = 2.6, df = 37, P <.05) were found. Women had briefer tolerance times and higher post-cold pressor ratings than men. When given gender-specific tolerance expectations, men and women did not differ in their pain tolerance, pain threshold, or pain ratings. This is the first empirical study to show that manipulation of expectations alters sex differences in laboratory pain.     

Hemodynamic and respiratory effects of dezocine, ciramadol, and morphine

The hemodynamic and respiratory effects of dezocine and ciramadol, two agonist-antagonist analgesics, were compared with those of morphine in 30 patients undergoing diagnostic cardiac catheterization. Each subject received a single intravenous dose of dezocine (0.125 mg/kg), ciramadol (0.6 mg/kg), or morphine (0.125 mg/kg) in a double-blind fashion. Hemodynamic and respiratory parameters were measured at baseline and 5, 10, and 20 minutes after dosing. Dezocine increased the cardiac index (CI; 2.67 to 2.92 L/min/m2), stroke volume index (SVI; 43.6 to 47.6 ml/beat/m2), left ventricular stroke work index (LVSWI; 57.4 to 64.7 gm-m/m2), and pulmonary vascular resistance (PVR; 105.6 to 154.0 dynes X sec/cm5). Ciramadol increased the CI (2.78 to 3.22 L/min/m2), SVI (40.9 to 48.2 ml/beat/m2), LVSWI (51.1 to 57.9 gm-m/m2), and mean pulmonary arterial pressure (PA; 14.7 to 18.9 mm Hg). Morphine had no effect on CI, SVI, LVSWI, PA, or PVR, but it significantly lowered systolic and diastolic blood pressures. There were no appreciable changes in heart rate, left ventricular end-diastolic pressure, mean arterial pressure, or mean pulmonary capillary wedge pressure after any of the drugs. All three drugs significantly decreased systemic vascular resistance. There were no clinically significant changes in respiratory parameters. We conclude that dezocine, ciramadol, and morphine have no clinically important adverse effects on cardiac performance.     

The effects of auricular transcutaneous electrical nerve stimulation (TENS) on experimental pain threshold and autonomic function in healthy subjects.

The present study examines the effects of auricular transcutaneous electrical nerve stimulation (TENS) on electrical pain threshold measured at the ipsilateral wrist and autonomic functions including skin temperature, blood pressure and pulse rate in 24 healthy subjects. TENS was administered as low frequency trains of pulses delivered at a 'strong but comfortable' intensity to 1 of 3 auricular points to be examined: (i) autonomic effects (autonomic point), (ii) pain threshold effects (wrist point), and (iii) placebo effects at an unrelated point (face point). A fourth untreated group was designated as a situation control. The main finding of the study was that auricular TENS produced no significant overall effects on experimental pain threshold or autonomic functions recorded under the present conditions. However, pain threshold was found to increase by over 50% of its pretreatment baseline in 4 subjects and by 30% in 6 subjects. This rise was not dependent upon the site of auricular TENS. The possible mechanisms of such changes are discussed.     

Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats.

Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence. This study investigated the site of action of the paradoxical effects of naltrexone and the generality of this effect. The potential of ultra-low doses of naltrexone to influence morphine-induced analgesia was investigated in tests of nociception. Administration of intrathecal (0.05 and 0.1 ng) or systemic (10 ng/kg i.p.) naltrexone augmented the antinociception produced by an acute submaximal dose of intrathecal (5 microg) or systemic (7.5 mg/kg i.p.) morphine in the tail-flick test. Chronic intrathecal (0.005 and 0.05 ng) or systemic (10 ng/kg) naltrexone combined with morphine (15 microg i.t.; 15 mg/kg i.p.) over a 7-day period inhibited the decline in morphine antinociception and prevented the loss of morphine potency. In animals rendered tolerant to intrathecal (15 microg) or systemic (15 mg/kg) morphine, administration of naltrexone (0.05 ng i.t.; 10 and 50 ng/kg i.p.) significantly restored the antinociceptive effect and potency of morphine. Thus, in ultra-low doses, naltrexone paradoxically enhances morphine analgesia and inhibits or reverses tolerance through a spinal action. The potential of naltrexone to influence morphine-induced reward was also investigated using a place preference paradigm. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference. These effects of naltrexone on morphine-induced reward may have implications for chronic treatment with agonist-antagonist combinations.