Reduction of conditioned pain modulation in humans by naltrexone: an exploratory study of the effects of pain catastrophizing

The current study tested the hypothesis that conditioned pain modulation is mediated by the release of endogenous opioids with a placebo-controlled (sugar pill) study of naltrexone (50 mg) in 33 healthy volunteers over two counter-balanced sessions. Pain modulation consisted of rating of heat pain (palm) during concurrent cold water immersion (foot). Compared to baseline heat pain ratings, concurrent foot immersion lowered pain intensity ratings, which suggests an inhibitory effect, was reduced with naltrexone, suggesting at least partial dependence of inhibition on endogenous opioids. An exploratory analysis revealed that individual differences in catastrophizing moderated the effects of naltrexone; endogenous opioid blockade abolished modulation in subjects lower in catastrophizing while modulation was unaffected by naltrexone among high catastrophizers. The results suggest a role of endogenous opioids in endogenous analgesia, but hint that multiple systems might contribute to conditioned pain modulation, and that these systems might be differentially activated as a function of individual differences in responses to pain.     

The psychobiology of hostility: Possible endogenous opioid mechanisms

This study examined the role of endogenous opioids in the relation between hostility and cardiovascular stress responsiveness. Forty-six men completed the Cook-Medley Hostility Scale and experienced a laboratory pain stressor once under opioid blockade and once under placebo. Hostility scores were significantly related to the magnitude of change in cardiovascular reactivity/recovery resulting from opioid blockade. Low scorers on the Cynicism subscale displayed increases in heart rate (HR) reactivity under blockade relative to placebo, with reactivity decreases noted in high scorers. Low Hostile Affect scores were similarly associated with impaired diastolic blood pressure recovery under opioid blockade. HR recovery results were somewhat different, with high scorers on Aggressive Responding and the total Cook-Medley displaying improved HR recovery under opioid blockade, with no change noted in low scorers. These data provide preliminary support for the hypothesis that low hostile individuals rely on endogenous opioids for buffering cardiovascular stress responsiveness, but high hostiles do not.     

Effects of Opioid Blockade with Naltrexone and Distraction on Cold and Ischemic Pain in Hypertension

Essential hypertension is characterised by reduced pain sensitivity. Hypertensive hypoalgesia has been attributed to elevated endogenous opioids and/or increased activation of descending pain modulation systems. A double-blind placebo-controlled design compared the effects of naltrexone and placebo on cold and ischemic pain in unmedicated newly-diagnosed patients with essential hypertension. Patients performed a cold pressor task while resting and while performing a distracting secondary task. They also performed a forearm ischemia task while resting. Although the cold pressor and ischemia tasks elicited significant increases in pain and blood pressure, pain ratings and pressor responses did not differ between naltrexone and placebo. Cold pain was reduced by distraction compared to rest. The finding that opioid blockade with naltrexone did not moderate the pain and pressor responses to cold and ischemia suggests that pain and associated blood pressure responses are not modulated by opioids in hypertension. The finding that the distracting secondary task successfully reduced pain ratings suggests normal supraspinal pain modulation in essential hypertension.     

Anger Management Style and Endogenous Opioid Function: Is Gender a Moderator?

This study explored possible gender moderation of previously reported associations between elevated trait anger-out and reduced endogenous opioid analgesia. One hundred forty-five healthy participants underwent acute electrocutaneous pain stimulation after placebo and oral opioid blockade in separate sessions. Blockade effects were derived reflecting changes in pain responses induced by opioid blockade. Hierarchical regressions revealed that elevated anger-out was associated with smaller pain threshold blockade effects (less opioid analgesia) in females, with opposite findings in males (interaction p < .001). Similar marginally significant interactions were noted for blockade effects derived for nociceptive flexion reflex threshold, pain tolerance, and pain ratings (p < .10). Anger-in was also associated negatively with pain threshold blockade effects in females but not males (interaction p < .05). Across genders, elevated anger-in was related to smaller pain tolerance blockade effects (p < .01). Overlap with negative affect did not account for these opioid effects. The anger-in/opioid association was partially due to overlap with anger-out, but the converse was not true. These findings provide additional evidence of an association between trait anger-out and endogenous opioid analgesia, but further suggest that gender may moderate these effects. In contrast to past work, anger-in was related to reduced opioid analgesia, although overlap with anger-out may contribute to this finding.     

Endogenous opioids and the first suckling episode in the rat

Endogenous activity at opioid receptors affects the appetitive behavior of Caesarean-delivered rat pups during presentation of a surrogate nipple that provides milk. Blockade of opioid receptors by peripheral injection of naloxone has no effect on responses evoked by the surrogate nipple. Similarly, blockade of caudal brain opioid receptors by injection of naloxone into the cisterna magna has no effect on the pup's behavior in response to the surrogate nipple. However, blockade of rostral opioid receptors by injection of naloxone into the cerebral ventricles increases the latency to the first oral grasp response, decreases total time on the nipple, and virtually eliminates ingestion of milk from the surrogate nipple (Experiment 1). Blockade of endogenous opioid activity does not affect responses to a nipple that provides distilled water (Experiment 2) or to an empty surrogate nipple (Experiment 3). These data indicate that during the initial suckling episode endogenous opioids in rostral brain regions affect the pup's behavioral responses to the nipple. The results are consistent with the hypothesis that milk engages opioid systems during the first suckling and that endogenous opioids play a role in early suckling. © 1998 John Wiley & Sons, Inc. Dev Psychobiol 33: 175–183, 1998     

Hypoalgesia associated with elevated resting blood pressure: evidence for endogenous opioid involvement

This study used a placebo-controlled, between-subjects opioid blockade design to evaluate endogenous opioid involvement in the hypoalgesia associated with elevated resting blood pressure (BP) in 163 healthy individuals. Participants were randomly assigned to Drug condition (placebo, naltrexone) and Task Order (computerized maze task with harassment followed by an ischemic pain task or vice versa). Resting BP was assessed, followed by drug administration, and then the pain and maze tasks. A significant Drug × Systolic BP (SBP) interaction was observed on McGill Pain Questionnaire-Affective pain ratings (P < .01), indicating that BP-related hypoalgesia observed under placebo was absent under opioid blockade. A significant Gender × Drug × SBP × Task Order interaction was observed for VAS pain intensity (P < .02). Examination of simple effects comprising this interaction suggested that BP-related hypoalgesia occurred only in male participants who experienced the pain task in the absence of emotional arousal, and indicated that this hypoalgesia occurred under placebo but not under opioid-blockade. Results suggest that under some circumstance, BP-related hypoalgesia may have an endogenous opioid-mediated component in healthy individuals, particularly men.     

Mechanisms of the Analgesic Effect of Corticotropin-Releasing Factor in Conscious Rats

We report here our studies of the contribution of the hypothalamo-hypophyseal-adrenocortical system (HHACS) and opioid system to the analgesic effect of corticotropin-releasing factor (CRF) in conscious rats exposed to thermal stimuli. Two methodological approaches were used: 1) blockade of the functional activity of the HHACS by administration of hydrocortisone at a pharmacological dose one week before experiments; 2) blockade of glucocorticoid receptors with the glucocorticoid receptor antagonist RU38486. The contribution of the opioid system was studied by blockade of opioid receptors with their antagonist naltrexone. Blockade of opioid receptors completely eliminated the analgesic effect of CRF, blockade of the functional activity of the HHACS decreased it, and blockade of glucocorticoid receptors increased the effect. These data provide evidence that the analgesic effect of CRF in conscious rats exposed to a thermal stimulus is mediated by an opioid-associated mechanism. The actions of opioids on pain sensitivity may be modulated by glucocorticoid hormones.     

Spinal opioid systems in inflammation

Until recently, basic science studies, both behavioural and electrophysiological, have concentrated on the antinociceptive actions of opioids primarily gauged against acute nociceptive responses. However, of more relevance to clinical situations are the actions of opioids in more persistent/prolonged pain states. This review sets out to examine the central actions of opioids against nociception of inflammatory origins. The first section deals with the response of the endogenous opioid system to the development of an inflammatory state and the second examines the ability of exogenous opioids to modulate inflammatory nociception. There are complex changes in the roles of endogenous opioids, in particular dynorphin, at the spinal level after inflammation although the physiological consequences remain unclear. With regard to exogenous opioids, the effectiveness of spinal morphine is rapidly enhanced after inflammation, likely to be due to changes in the interaction between the peptide cholecystokinin and the mu opioid receptor. The ability of inflammatory processes to alter both endogenous opioids and morphine analgesia at the spinal level illustrates the considerable degree of plasticity observed in opioid function.     

Nociceptive flexion reflex and pain rating responses during endogenous opiate blockade with naltrexone in healthy young adults

The effect of opioid blockade on nociceptive flexion reflex (NFR) activity and subjective pain ratings was examined in 151 healthy young men and women. Using a within-subjects design, NFR threshold was assessed on 2 days after administration of either placebo or a 50mg dose of naltrexone. Electrocutaneous pain threshold and tolerance levels were measured after NFR threshold assessment on each day. Results indicated that administration of naltrexone was consistently associated with hypoalgesic responding. Specifically, participants exhibited lower levels of NFR activity and reported lower pain ratings for electrocutaneous stimulation delivered at pain threshold and tolerance levels following administration of naltrexone as compared to placebo. These findings indicate that opiate blockade using the current standard dose may elicit hypoalgesia. A potential moderating effect of dose of opiate-blockade medication and level of endogenous opioid activation should be carefully examined in future research.     

Naltrexone potentiates glycemic responses during stress and epinephrine challenge in genetically obese mice

The genetically obese mouse (C57BL/6J ob/ob) is a commonly used animal model of non-insulin-dependent diabetes mellitus. These mice show exaggerated glycemic responses during behavioral stress and adrenergic stimulation, but the precise glucoregulatory mechanisms are not well characterized. The ob/ob mice have multiple endocrine abnormalities, including elevated pituitary and circulating beta-endorphin levels; and a relationship between hyperglycemia and altered opioid function has been suspected. We now report that opiate antagonism with naltrexone potentiates hyperglycemic responses during stress and epinephrine challenge in obese mice. This effect of opioid blockade suggests that endogenous opioids inhibit stress- and epinephrine-induced hyperglycemia in the genetically obese mouse.     

Opioid mediation of odor preferences induced by sugar and fat in 6-day-old rats.

Intraoral infusions of sucrose, fat or polycose reduce ultrasonic vocalizations during isolation, and increase pain threshold in infant rats. These effects are naltrexone reversible. The present study determined whether these substances, when paired with an odor, caused a change in preference for that odor. In 6-day-old rats, pairing orange odor with intraoral infusions of sucrose or corn oil, but not polycose, water, mineral oil or 0.01% quinine hydrochloride, caused a substantial increase in preference for orange. Preference formation was blocked by systemic injection of naltrexone (0.25 mg/kg) prior to pairing orange with either sucrose or corn oil. Moreover, preference expression was prevented by naltrexone injection prior to testing. Thus certain substances thought to reduce stress in infant rats via endogenous opioid release can also cause preference for substances that predict their occurrence. Preference formation depends upon the availability of endogenous opioids. Preference expression reflects the conditioned stimulus causing opioid release.     

Assessment of opiate modulation of pain and nociceptive responding in young adults with a parental history of hypertension

This double blind, placebo-controlled study examined the effects of an opiate antagonist, naltrexone, on nociceptive flexion reflex (NFR) thresholds and subjective pain in individuals with and without a parental history of hypertension. Using a repeated measures design, NFR threshold was repeatedly assessed on two testing days after administration of either placebo or naltrexone. Immediately after NFR threshold was determined, participants rated the level of pain experienced during the preceding NFR assessment, and at the end of each session participants’ electrocutaneous pain threshold was assessed. Two primary findings were obtained. First, individuals with a parental history of hypertension exhibited attenuated pain sensitivity. Second, endogenous opioid blockade was associated with increased pain ratings in women but with increased pain threshold in men. In sum, the present study did not support a direct involvement of the endogenous opioid system in the attenuated pain sensitivity observed in individuals at increased risk for hypertension.     

Effects of baroreceptor stimulation and opioids on the auditory startle reflex

We examined (a) whether carotid baroreceptor stimulation attenuates the auditory startle response and its modulation by preceding affective pictures, and (b) whether these effects are mediated by endogenous opioids. Seventy-eight young normotensive adults with or without a parental history of hypertension received brief exposures to affective pictures and noise bursts during phasic manipulation of the carotid baroreceptors. In each participant, opioids were blocked by naltrexone in half of the sessions. Baroreceptor stimulation had a strong dampening effect on the startle response. This effect was not influenced by opioid blockade, sex, or parental history of hypertension. No baroreceptor effects were obtained regarding ratings of the affective pictures or startle modulation by the pictures. The baroreceptor stimulation effects seem to be mediated by the basal primary acoustic startle circuit rather than by higher affective circuits.     

Anger Management Style,Opioid Analgesic Use,and Chronic Pain Severity: A Test of the Opioid-Deficit Hypothesis

Anger management style is related to both acute and chronic pain. Recent research suggests that individuals who predominantly express anger (anger-out) may report heightened chronic pain severity due in part to endogenous opioid antinociceptive dysfunction. If exogenous opioids serve to remediate opioid deficits, we predicted that regular use of opioid analgesics by chronic pain patients would alter these relationships such that anger-out would be related to chronic pain severity only among opioid-free patients. For 136 chronic pain patients, anger management style, depression, anxiety, pain severity, and use of opioid and antidepressant medication was assessed. Results of hierarchical multiple regressions to predict chronic pain severity showed: (a) a significant Anger-out × Opioid use interaction such that high Anger-out was associated with high pain severity only among patients not taking opioids; (b) controlling for depressed affect and anxiety did not affect this association; (c) the Anger-out × Antidepressant use interaction was nonsignificant; (d) Anger-in did not interact with use of any medication to affect pain severity. Results are consistent with an opioid-deficit hypothesis and suggest that regular use of opioid medications by patients high in anger expression may compensate for an endogenous opioid deficit, and mitigate the effects of elevated anger expression on chronic pain intensity.     

Opioid modulation of reflex versus operant responses following stress in the rat

In pre-clinical models intended to evaluate nociceptive processing, acute stress suppresses reflex responses to thermal stimulation, an effect previously described as stress-induced "analgesia." Suggestions that endogenous opioids mediate this effect are based on demonstrations that stress-induced hyporeflexia is enhanced by high dose morphine (>5 mg/kg) and is reversed by naloxone. However, reflexes and pain sensations can be modulated differentially. Therefore, in the present study direct comparisons were made of opioid agonist and antagonist actions, independently and in combination with acute restraint stress in Long Evans rats, on reflex lick-guard (L/G) and operant escape responses to nociceptive thermal stimulation (44.5 degrees C). A high dose of morphine (>8 mg/kg) was required to reduce reflex responding, but a moderate dose of morphine (1 mg/kg) significantly reduced escape responding. The same moderate dose (and also 5 mg/kg) of morphine significantly enhanced reflex responding. Naloxone (3 mg/kg) significantly enhanced escape responding but did not affect L/G responding. Restraint stress significantly suppressed L/G reflexes (hyporeflexia) but enhanced escape responses (hyperalgesia). Stress-induced hyperalgesia was significantly reduced by morphine and enhanced by naloxone. In contrast, stress-induced hyporeflexia was blocked by both naloxone and 1 mg/kg of morphine. Thus, stress-induced hyperalgesia was opposed by endogenous opioid release and by administration of morphine. Stress-induced hyporeflexia was dependent upon endogenous opioid release but was counteracted by a moderate dose of morphine. These data demonstrate a differential modulation of reflex and operant outcome measures by stress and by separate or combined opioid antagonism or administration of morphine.     

Effects of naltrexone on electrocutaneous pain in patients with hypertension compared to normotensive individuals

An opioid mechanism may help explain hypertensive hypoalgesia. A double-blind placebo-controlled design compared the effects of opioid blockade (naltrexone) and placebo on electrocutaneous pain threshold, pain tolerance, and retrospective McGill Pain Questionnaire ratings in 35 unmedicated patients with essential hypertension and 28 normotensive individuals. The hypertensives experienced less pain than normotensives during the assessment of their pain tolerance; however, this manifestation of hypertensive hypoalgesia was not moderated by naltrexone. These findings fail to support the hypothesis that essential hypertension is characterised by relative opioid insensitivity.     

Evidence for opioid and nonopioid processes mediating adaptive responses of infant rats that are repeatedly isolated

Previous research examining the ability of neonatal rats to adapt to repeated isolation demonstrated that an opioid-dependent decline in ultrasonic vocalizations occurred across a series of isolations (Goodwin, Molina, & Spear, 1994). These findings were expanded in the present study. In the first experiment, the decline in vocalization rates was found to result from the release of endogenous opioids throughout the series of isolations. Although naltrexone attenuated the decline in calling rates relative to vehicle-treated subjects, there was still a significant decline in calling rates following opioid receptor blockade. In the second experiment, two injections of naltrexone did not attenuate the decline in calling rates any more than a single injection did, suggesting that there must also be some nonopioid process that modulates this decline. In both experiments, activity levels and, in the first experiment, the amount of body heat lost in the repeatedly isolated subjects declined in a nonnaltrexone reversible manner. In a final study, after calling rates had been suppressed by a series of isolations, a brief exposure to the mother was found to restore baseline calling rates, suggesting the decline is not the consequence of fatigue. The attenuation of vocalization rates, activity, and loss of body heat are adaptive responses of infant rats to isolation; however, of these three, only the attenuation of vocalization rates is consistently modulated by the release of endogenous opioids. © 1997 John Wiley & Sons, Inc. Dev Psychobiol 31: 217–227, 1997     

Anger Regulation Style, Postoperative Pain, and Relationship to the A118G Mu Opioid Receptor Gene Polymorphism: A Preliminary Study

Greater trait anger-out is associated with elevated pain responsiveness. Previous work suggests this effect may be mediated by deficient endogenous opioid analgesia, possibly reflecting diminished opioid receptor sensitivity. The A118G single nucleotide polymorphism (SNP) of the mu opioid receptor gene influences both opioid receptor sensitivity and clinical responsiveness to opioid analgesics. Therefore, this study tested whether this SNP either mediated or moderated the effects of anger-out on postsurgical pain outcomes. Forty-eight patients undergoing coronary artery bypass graft surgery provided genetic samples, and completed measures of anger-out and postsurgical pain. Postsurgical opioid analgesic use was also recorded. Anger-out was positively associated with postsurgical pain ratings (p < 0.05). Anger-out was not associated with A118G SNP status (p > 0.10), suggesting the latter is unlikely to mediate anger-out's pain-related effects. A significant anger-out × A118G interaction was observed on analgesic use (p < 0.05), due to a much stronger positive relationship between anger-out and analgesic demands in patient with the A118G SNP (b = 0.53) than those with the wild-type receptor (b = 0.07). These results suggest that the A118G SNP may moderate but not mediate the effects of anger-out on postoperative pain responses.     

Blood Pressure Reactivity and Perception of Pain During the Forehead Cold Pressor Test

The relationship between blood pressure reactivity and the perception of pain was examined during a series of three forehead cold pressor tests given every other day to a group of 18 male college students. Subjects classified as high reactors on the basis of peak increases in mean blood pressure during cold pressor tests perceived the cold pressor stimulus as more painful than subjects classified as low reactors. The propensity to rate the cold pressor stimulus as painful was positively correlated with the individual level of blood pressure reactivity (baseline-free partial r = .62). Intra-individual correlations between pain and blood pressure responses were unrelated to subjects' reactivity status. Across the 3-min test, correlations between pain and blood pressure reactivity (with the effects of baseline blood pressure levels partialled out) were significant only during periods when levels of responses were relatively high. The heart rate responses were unrelated to pain ratings. Generalizability theory was applied to the analysis of temporal stability of cold pressor reactions. Both blood pressure and pain responses were highly reproducible across three sessions, appearing to express stable individual differences. The efficacy of 800 mg oral ibuprofen in controlling the cold pressor pain was also tested. Analgesic activity of the drug during the cold pressor test could not be demonstrated.