***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Summary Individual differences in endogenous opioid function predict morphine analgesic responses  , and these endogenous opioid differences mediate the association between greater laboratory‐evoked pain sensitivity and greater analgesic responses to morphine . ABSTRACT Predictors of responsiveness to opioid analgesic medications are not well understood . This study tested whether individual differences in endogenous opioid ( EO ) function are associated with analgesic responsiveness to morphine . In r and omized , counterbalanced order over 3 sessions , 45 chronic low back pain participants and 31 healthy controls received an opioid antagonist ( 8 mg naloxone ) , morphine ( 0.08 mg/kg ) , or placebo . Participants then engaged in 2 laboratory‐evoked pain tasks ( ischemic and thermal ) . Outcomes included pain threshold , pain tolerance , and pain ratings . Indexes of EO function and morphine analgesic responsiveness were derived for each measure as the difference in pain responses between the placebo condition and naloxone or morphine condition , respectively . For all 7 pain measures across the 2 laboratory pain tasks , greater EO function was associated with significantly lower morphine analgesic responsiveness ( P < 0.001–P = 0.02 ) . Morphine reduced pain responses of low EO individuals to levels similar to those of high EO individuals receiving placebo . Higher placebo condition – evoked pain sensitivity was associated with significantly greater morphine analgesic responsiveness for 5 of 7 pain measures ( P < 0.001–P = 0.02 ) . These latter associations were significantly mediated by EO function for 4 of these 5 pain outcomes ( all P values < 0.05 ) . In the laboratory‐evoked pain context , opioid analgesic medications may supplement inadequate EO analgesia , with little incremental benefit in those with preexisting high EO function . Implication s for personalized medicine are discussed THE discovery of opiate-like peptides ( endorphins ) in brain , blood and cerebrospinal fluid1–4 raises questions as to the physiological role of these substances . Given the prominent analgesic effects of opiates , the regulation of pain perception is a c and i date for endorphin action . Endorphins microinjected into the periacqueductal grey matter of rats induce analgesia which is reversed by naloxone , a pure narcotic antagonist5 . If endorphins play an active part in the regulation of pain , then naloxone administered to man should alter pain appreciation . Naloxone has not been shown to have analgesic , respiratory , euphoric , pupillary or electroencephalogram ( EEG ) effects in man6 . Studies in rats7,8 and one early study in man9 have suggested slight hyperalgesic effects with naloxone . El-Sobky et al.10 failed to demonstrate naloxone effects on electric shock pain judgments in five subjects . In the experiments reported here , subjects were divided into  pain sensitive and pain insensitive subgroups . The insensitive subjects found shocks significantly more painful after naloxone administration while the sensitive group experienced them as less painful . Evoked potentials showed similar significant group differences . These results suggest that individual differences in pain sensitivity may relate to differences in an endorphin system Purpose Opioid therapy is associated with the development of tolerance and paradoxically increased sensitivity to pain . It has been suggested that buprenorphine is associated with a higher antihyperalgesia/analgesia ratio than μ-opioid receptor agonists . The primary outcome of this study was therefore to investigate relative differences in antihyperalgesia and analgesia effects between morphine and buprenorphine in an inflammatory pain model in volunteers . The secondary outcome was to examine the relationship between pain sensitivity and opioid-induced effects on analgesia , antihyperalgesia , and descending pain modulation . Subjects and methods Twenty-eight healthy subjects were included . The study was a double-blind , r and omized , placebo-controlled , five-arm crossover study with a multimodal ( electrical , mechanical , and thermal stimuli ) testing technique . After baseline assessment s , intravenous infusions of morphine ( 10/20 mg ) , buprenorphine ( 0.3/0.6 mg ) , or placebo ( normal saline ) were administered over a 210-minute period , during which a cold pressor test , heat injury ( 47 ° C , 7 minutes , 12.5 cm2 ) , and the first postburn assessment were done . After completion of the drug infusions , two additional postburn assessment s were done . The subjects were monitored during each 8-hour session by an anesthesiologist . Results For nearly all tested variables , significant dose-dependent analgesic effects were demonstrated . The median antihyperalgesia/analgesia ratio ( secondary hyperalgesia/heat injury relative to placebo ) for low-dose morphine was 0.01 ( interquartile range : −6.2 ; 9.9 ) , 0.00 ( −2.4 ; 2.1 ) for high-dose morphine , 0.03 ( −1.8 ; 2.1 ) for low-dose buprenorphine , and 0.00 ( −3.2 ; 1.1 ) for high-dose buprenorphine ( P > 0.466 ) . There were no significant differences in opioid responses between high and low pain-sensitive subjects ( P > 0.286 ) . High-dose buprenorphine , compared to placebo , was associated with a significantly enhanced action of the descending inhibitory pain control system ( P = 0.004 ) . Conclusion The present study , using multimodal testing technique , could not demonstrate any significant differences between morphine and buprenorphine in the profiles of antihyperalgesia and analgesia . Only high-dose buprenorphine was associated with a significant effect on the descending inhibitory pain control system & NA ; We investigated the role of endogenous opioid systems in the analgesic effects induced by repetitive transcranial magnetic stimulation ( rTMS ) . We compared the analgesic effects of motor cortex ( M1 ) or dorsolateral prefrontal cortex ( DLPFC ) stimulation before and after naloxone or placebo treatment , in a r and omized , double‐blind crossover design , in healthy volunteers . Three groups of 12 volunteers were selected at r and om and given active stimulation ( frequency 10 Hz , at 80 % motor threshold intensity , 1500 pulses per session ) of the right M1 , active stimulation of the right DLPFC , or sham stimulation , during two experimental sessions 2 weeks apart . Cold pain thresholds and the intensity of pain induced by a series of fixed‐temperature cold stimuli ( 5 , 10 , and 15 ° C ) were used to evaluate the analgesic effects of rTMS . Measurements were made at the left thenar eminence , before and 1 hour after the intravenous injection of naloxone ( bolus of 0.1 mg/kg followed by a continuous infusion of 0.1 mg/kg/h until the end of rTMS ) or placebo ( saline ) . Naloxone injection significantly decreased the analgesic effects of M1 stimulation , but did not change the effects of rTMS of the DLPFC or sham rTMS . This study demonstrates , for the first time , the involvement of endogenous opioid systems in rTMS‐induced analgesia . The differential effects of naloxone on M1 and DLPFC stimulation suggest that the analgesic effects induced by the stimulation of these 2 cortical sites are mediated by different mechanisms . Endogenous opioids are shown to be involved in the analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex The pathophysiological mechanisms underlying fibromyalgia are still unknown , although some evidence points to endogenous opioid dysfunction . We examined how endogenous opioid antagonism affects pain and mood for women with and without fibromyalgia . Ten women with fibromyalgia and ten age- and gender-matched , healthy controls each attended two laboratory sessions . Each participant received naltrexone ( 50 mg ) at one session , and placebo at the other session , in a r and omized and double-blind fashion . Participants were tested for changes in sensitivity to heat , cold , and mechanical pain . Additionally , we collected measures of mood and opioid withdrawal symptoms during the laboratory sessions and at home the night following each session . At baseline , the fibromyalgia group exhibited more somatic complaints , greater sensory sensitivity , more opioid withdrawal somatic symptoms , and lower mechanical and cold pain-tolerance than did the healthy control group . Neither group experienced changes in pain sensitivity due to naltrexone administration . Naltrexone did not differentially affect self-reported withdrawal symptoms , or mood , in the fibromyalgia and control groups . Consistent with prior research , there was no evidence found for abnormal endogenous opioid activity in women with fibromyalgia IF endorphins modulate pain , then naloxone should affect pain behaviour even in subjects who have not received exogenous opiates . However , some naloxone studies cl aim a lack of effect1,2 , others a hyperalgesic effect3–5 , and others both hyperalgesic and analgesic effects6,7 . Such discrepancies may arise from the different methods used to induce and assess pain8 , and from variation in dose . We know of only one previous human study which used multiple doses of naloxone6 ; this indicated a dose-dependent bi-directional effect . In the present study , a clinical pain paradigm was used to generate a dose – response curve for naloxone . We report that naloxone produces analgesia at low doses and hyperalgesia at high doses Introduction Development of secondary hyperalgesia following a cutaneous injury is a central ly mediated , robust phenomenon . The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear . Recent animal studies , carried out after the resolution of inflammatory pain , have demonstrated reinstatement of tactile hypersensitivity following administration of μ-opioid-receptor-antagonists . In the present study in humans , we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury . Methods Twenty-two healthy volunteers were included in this placebo-controlled , r and omized , double-blind , cross-over study . Following baseline assessment of thermal and mechanical thresholds , a first-degree burn injury ( BI ; 47 ° C , 7 minutes , thermode area 12.5 cm2 ) was induced on the lower leg . Secondary hyperalgesia areas around the BI-area , and separately produced by brief thermal sensitization on the contralateral thigh ( BTS ; 45 ° C , 3 minutes , area 12.5 cm2 ) , were assessed using a polyamide monofilament at pre-BI and 1 , 2 , and 3 hours post-BI . At 72 hrs , BI and BTS secondary hyperalgesia areas were assessed prior to start of a 30 minutes intravenous infusion of naloxone ( total dose 21 microg/kg ) or placebo . Fifteen minutes after start of the infusion , BI and BTS secondary hyperalgesia areas were reassessed , along with mechanical and thermal thresholds . Results Secondary hyperalgesia areas were demonstrable in all volunteers 1–3 hrs post-BI , but were not demonstrable at 72 hrs post-burn in 73–86 % of the subjects . Neither magnitude of secondary hyperalgesia areas nor the mechanical and thermal thresholds were associated with naloxone-treated compared to placebo-treated subjects . Conclusion Naloxone ( 21 microg/kg ) did not reinstate secondary hyperalgesia when administered 72 hours after a first-degree burn injury and did not increase BTS-generated hyperalgesia . The negative results may be due to the low dose of naloxone or insufficient tissue injury to generate latent sensitization In fMRI there are two classes of inference : one aims to make a comment about the " typical " characteristics of a population , and the other about " average " characteristics . The first pertains to studies of normal subjects that try to identify some qualitative aspect of normal functional anatomy . The second class necessarily applies to clinical neuroscience studies that want to make an inference about quantitative differences of a regionally specific nature . The first class of inferences is adequately serviced by conjunction analyses and fixed-effects models with relatively small numbers of subjects . The second requires r and om-effect analyses and larger cohorts & NA ; We investigated the role of the glutamatergic and endogenous opioidergic systems in the paradoxical pain  evoked by the simultaneous application of innocuous warm and cold stimuli to the skin with a “ thermal grill ” . Two parallel r and omized , double‐blind , cross‐over studies , including two groups of 12 healthy volunteers , were carried out to compare the effects of i.v . ketamine or naloxone to those of placebo , on the sensations produced by a thermode ( i.e. thermal grill ) composed of six bars applied on the palmar surface of the right h and . The temperature of alternate ( even‐ and odd‐numbered ) bars could be controlled independently by Peltier elements to produce various patterns of the grill . During each experimental session we measured the effects of ketamine , naloxone or placebo on the intensity of : ( i ) paradoxical pain ; ( ii ) “ normal ” thermal ( heat and cold ) pain ; and ( iii ) non‐painful thermal ( warm and cool ) sensations . Ketamine administration result ed in a significant reduction of paradoxical pain intensity but did not alter normal pain or non‐painful thermal sensations . By contrast , naloxone had no effect on paradoxical pain , normal pain or non‐painful thermal sensations . This study demonstrates for the first time that the “ thermal grill illusion of pain ” can be modulated pharmacologically . This paradoxical pain , which involves the glutamatergic systems , acting through the N 
    Output:
    
In conclusion , only in 2 experimental human pain models , i.e. , stress-induced analgesia and rTMS , administration of MOR-antagonist demonstrated a consistent effect , presumably mediated by an EOS-dependent mechanisms of analgesia and hyperalgesia