Elevated Pain Thresholds Research Articles

Influence of gender and hemispheric lateralization on heat pain perception in major depression

Increased incidence of clinical pain complaints from patients with major depression, as well as increased experimental pain thresholds have been reported. The basis of this phenomenon remains unclear, as well as its relation to medication, clinical recovery, gender and lateralization of hemispheric function. We aimed to further elucidate heat pain perception in depression applying a testing battery including assessment (on both arms) of warmth perception, heat pain perception and heat pain tolerance, and the jaw opening reflex (duration of ES2 component) as a putative indicator of descending pain inhibition. The battery was applied to 20 patients and 20 age- and sex-matched controls. Patients were assessed: on admission (acutely depressed, off-medication), few days after admission (depressed, on medication), and after clinical recovery (mostly on medication), and controls at corresponding intervals. Significant elevated heat pain thresholds were found off and on medication in the acute stage (mainly in women) and after recovery on the right arm only. Elevated heat pain tolerance (on the right arm only) was seen in medicated patients in the acute and recovered stage. Significant prolongation of ES2 duration was only found in acutely depressed patients off medication. While confirming hypalgesia to heat pain in major depression, our findings demonstrate a close relation to gender and strong influence of lateralization after recovery. Altered pain processing at brain stem level might only partially be responsible for the observed finding.

Electroporation-mediated pain-killer gene therapy for mononeuropathic rats.

The relatively low expression levels achieved from transferred genes have limited the application of nonviral vectors for gene transfer into the spinal cord in vivo. Thus, the aim of this study was to evaluate the efficacy of electroporation-mediated pro-opiomelanocortin (POMC) gene therapy for neuropathic pain using an animal model of chronic constrictive injury (CCI). Firstly, the optimal pulse characteristics (voltage, pulse duration, number of shocks) were investigated for in vivo electroporation-mediated gene transfer into the spinal cord. The electroporation process makes use of plasmid DNA, which expresses the POMC gene. Expression levels were evaluated in this study by Western blot. We conclude that the optimal conditions for electroporation are a pulse voltage of 200 V, 75-ms duration, 925-ms interval, for five iterations. Secondly, electroporation treatment for neuropathic pain was attempted on CCI rats using plasmid DNA that expresses the POMC gene. Intrathecal administrations of the POMC vector elevated spinal beta-endorphin levels, as manifested in a significantly elevated pain threshold for the CCI limbs. This result suggests that gene therapy for neuropathic pain using this novel technique is very efficacious, and thus shows promise for further clinical trials.

Analgesic and anti-inflammatory effects of the aqueous extract of leaves of Persea americana Mill (Lauraceae)

The aqueous extract of Persea americana leaves produced a dose-dependent inhibition of both phases of formalin pain test in mice, a reduction in mouse writhing induced by acetic acid and an elevation of pain threshold in the hot plate test in mice. The extract also produced a dose-dependent inhibition of carrageenan-induced rat paw oedema. The results obtained indicate that the extract possesses analgesic and anti-inflammatory effects.

Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity

The pain modulatory role of dopamine D2 receptors of the human forebrain was studied by determining the association between dopamine D2 receptor binding potential and the response to experimental pain. Nineteen healthy male volunteers participated in a dopamine D2 receptor positron emission tomography study. The extrastriatal regions of interest studied with [ 11C]FLB 457 as radioligand ( n=11) were the anterior cingulum, the medial and lateral thalamus, the medial and lateral frontal cortex, and the medial and lateral temporal cortex. The striatal regions of interest studied with [ 11C]raclopride ( n=8) were the caudate nucleus and the putamen. The latency to the ice water-induced cold pain threshold and tolerance were determined in a separate psychophysical test session. Moreover, the cutaneous heat pain threshold and its elevation by concurrent cold pain in the contralateral hand were determined in each subject. Cold pain threshold was inversely correlated with D2 binding potential in the right putamen and the cold pain tolerance was inversely correlated with D2 binding potential in the right medial temporal cortex. The magnitude of heat pain threshold elevation induced by concurrent cold pain was directly correlated with D2 binding potential in the left putamen. Other correlations of D2 binding potentials in varying brain regions with sensory responses were not significant. A psychophysical control study ( n=10) showed that cold pain responses were identical in the right and left hand. The results indicate that dopamine D2 receptor binding potential in the human forebrain, particularly in the striatum, may be an important parameter in determining the individual cold pain response and the potential for central pain modulation. Accordingly, an individual with only few available D2 receptors in the forebrain is likely to have a high tonic level of pain suppression, combined with a low capacity to recruit more (dopaminergic) central pain inhibition by noxious conditioning stimulation.

Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain

Patients with sensory disturbances of painful and non-painful character show distinct changes in touch and/or pain sensitivity. The patterns of sensory changes were compared to those of human surrogate models of neuropathic pain to assess the underlying mechanisms. We investigated 30 consecutive in-patients with dysaesthesia of various origins (peripheral, spinal, and brainstem lesions) and 15 healthy subjects. Tactile thresholds were determined with calibrated von Frey hairs (1.1 mm ∅). Thresholds and stimulus–response functions for pricking pain were determined with a series of calibrated punctate mechanical stimulators (0.2 mm ∅). Allodynia was tested by light stroking with a brush, Q-tip, and cotton wisp. Perceptual wind-up was tested by trains of punctate stimuli at 0.2 or 1 Hz. Intradermal injection of capsaicin ( n=7) and A-fiber conduction blockade ( n=8) served as human surrogate models for neurogenic hyperalgesia and partial nociceptive deafferentation, respectively. Patients without pain (18/30) showed a continuous distribution of threshold shifts in the dysaesthetic skin area with a low to moderate increase in pain threshold (by 1.52±0.45 log 2 units). Patients with painful dysaesthesia presented as two separate groups (six patients each): one showing lowered pain thresholds (by −1.94±0.46 log 2 units, hyperalgesia) and the other elevated pain thresholds (by 3.02±0.48 log 2 units, hypoalgesia). The human surrogate model of neurogenic hyperalgesia revealed nearly identical leftward shifts in stimulus–response function for pricking pain as patients with spontaneous pain and hyperalgesia (by a factor of about 5 each). The sensory changes in the human surrogate model of deafferentation were similar to patients with hypoalgesia and spontaneous pain (rightward shift of the stimulus–response function with a decrease in slope). Perceptual wind-up did not differ between symptomatic and control areas. There was no exclusive association of any parameter obtained by quantitative sensory testing with a particular disease (of either peripheral or central origin). Our findings suggest that neuropathic pain is based on two distinct mechanisms: (I) central sensitization (neurogenic hyperalgesia; in patients with minor sensory impairment) and (II) partial nociceptive deafferentation (painful hypoalgesia; in patients with major sensory deficit). This distinction as previously postulated for postherpetic neuralgia, is obviously valid also for other conditions. Our findings emphasize the significance of a mechanism-based classification of neuropathic pain.

Thermotactile threshold testing for the evaluation of sensory nerve function in vibration-exposed patients and workers.

The aim of the present study was to ascertain the usefulness of thermotactile testing under the measuring conditions clarified by our previous study in the evaluation of vibration-induced neuropathy. Thermal (warm and cold) thresholds were examined on the index fingers of both hands of ten patients with hand-arm vibration syndrome, 36 workers exposed to hand-transmitted vibration, and ten healthy controls, using an aesthesiometer under the following measuring conditions: change rate of the applicator temperature was fixed at a rate of 1 degrees C/s; finger contact force on the applicator was kept at 0.5 N; and forearm was positioned on a support. Vibrotactile thresholds at 125 Hz and pain thresholds were also measured on the index fingers. Both warm and cold thresholds had more severely deteriorated in the patients than in the controls. Vibrotactile and pain thresholds were also increased in the patients. In the vibration-exposed workers, the neutral zone between the warm and cold threshold differed from in the controls. Thermotactile thresholds were likely to have deteriorated with advanced nerve impairment. Likelihood ratios of thermotactile testing were significantly high between the patients and the controls. For vibration-exposed workers with elevated vibrotactile and pain thresholds, the ratios were also significantly high, particularly in the neutral zone, though the accuracy tended to be lower than in the patients. Thermotactile thresholds appeared to be more closely correlated with pain thresholds than vibrotactile thresholds. Thermotactile threshold testing under the present measuring conditions can be useful for evaluating small sensory nerve fibre dysfunction in vibration-exposed subjects, and the neutral zone may be a sensitive indicator in vibration-exposed workers who may have slight or mild nerve impairments.

Antinociceptive effect following dietary-induced thiamine deficiency in mice: Involvement of substance P and somatostatin

We produced thiamine deficiency by treating mice with a thiamine deficient (TD) diet, but not with pyrithiamine, a thiamine antagonist. Twenty days after TD feeding, a significant antinociceptive effect was observed in the formalin test. A single injection of thiamine HCl (50 mg/kg, s.c.) on the 19th day after TD feeding (on the late TD stage) failed to reverse the antinociceptive effect, the muricide effect, and impairment of avoidance learning induced by TD feeding, as compared to pair-fed controls. These results indicate the possibility that the TD-induced antinociceptive effect may result from irreversible changes in the spinal and/or brain neurons. To clarify the involvement of substance P (SP) and somatostatin (SST) systems in the spinal cord, we examined the effect of intrathecal (i.t.) injections of these agonists on TD feeding-inducd elevation of pain threshold. I.t. injection of SP and SST elicited a behavioral response consisting of reciprocal hindlimb scratching, biting and/or licking of hindpaws. There was no significant difference in the behavioral response to SP between TD mice and PF mice on the 5th day after feeding. However, on the 10th and 20th day after TD feeding the response to SP was significantly increased compared with PF mice. This phenomenon was also observed with SST on the 20th day after TD feeding. These results indicate the possibility that TD feeding may produce an increased behavioral response to SP and SST through an enhanced sensitivity of neurokinin-1 and SST receptors in the spinal cord. Taken together, the antinociceptive effect following TD feeding may result from a decrease in spinal SP and SST contents.

Pain insensitivity in the relatives of schizophrenia patients

The psychiatric literature contains anecdotal reports of diminished pain sensitivity in schizophrenia that date back to Kraepelin. Yet, the phenomenon of pain insensitivity in schizophrenia remains largely unstudied. For example, it is not clear if pain insensitivity is a consequence of the illness or if it is also present in the well relatives of schizophrenia patients. To explore this issue, we examined pain thresholds and pain tolerances in healthy young adults. Compared with controls with no family history of psychopathology ( n=21), participants with a family history of schizophrenia ( n=32) showed elevated pain thresholds and pain tolerances to finger pressure. Pain insensitivity was also significantly correlated with elevated scores on measures of self-referential thinking, magical ideation, and perceptual disturbances. Finally, a sizeable minority (19%) of well relatives of schizophrenia patients showed extreme pain insensitivity compared to other participants. The pattern of findings suggests that pain insensitivity may warrant further exploration as a potential marker of underlying liability to psychosis.

Effect of ACTH on pain sensitivity in rats.

Systemic administration of ACTH to rats with normal hormone production induced a rapid (started 3 min postinjection) and long-term (persisted 30 min) elevation of pain threshold. Complete inhibition of glucocorticoid production shortened the duration of ACTH-induced analgesia to 15 min. The biphasic effect of ACTH on pain sensitivity is probably mediated by short-term glucocorticoid-independent and long-term glucocorticoid-dependent mechanisms.

Effects of human placental extract on chemical and thermal nociception in mice

Several reports indicate that pregnancy and parturition are associated with elevated maternal pain thresholds to noxious stimuli. The objective of this study was to examine whether the human placental extract, a clinically used preparation, can inhibit experimental nociception. Nociception was assessed in mice using acetic acid-induced writhing and hot-plate tests. The human placental extract (200 and 400 mg/kg, i.p.) elicited dose-related antinociception in the acetic acid-induced writhing test. Furthermore, it (200 mg/kg, i.p.) potentiated the morphine-induced antinociception (1.25 mg/kg, s.c.). In the hot-plate test, the human placental extract (100, 200 and 400 mg/kg, i.p.) per se, displayed no significant antinociception but potentiated the duration of morphine (10 mg/kg, s.c.) analgesia. The potentiation by the extract of the morphine-induced antinociception in both acetic acid and hot-plate tests was, however, found to be naloxone sensitive. Mice treated with the extract (400 mg/kg, i.p.) neither manifested any overt behavioural change in the open-field test nor demonstrated significant influence on pentobarbital sleeping time, suggesting that it has no central depressant or sedative activity. The data provide evidence to show that the human placental extract has a peripheral analgesic property possibly mediated by an opioid mechanism.

Acute pain threshold in subjects with chronic pain following spinal cord injury

Studies of pain perception in patients with chronic pain have yielded contradictory results. While several studies found that acute pain threshold is raised in chronic pain subjects, others showed that these subjects exhibit a decreased pain threshold compared to pain free subjects. The aim of this study was to further examine this topic by studying pain perception in subjects with chronic pain following partial or complete spinal cord injury (SCI). We found a significant elevation of heat-pain threshold (measured above the level of lesion) in complete SCI subjects with chronic pain (CSCIP) as opposed to complete SCI subjects without pain, incomplete SCI subjects with (ISCIP) and without chronic pain and normal controls. This elevation of pain threshold was completely reversed following a complete relief of the chronic pain by DREZ lesion. Moreover, the CSCIP exhibited significantly higher scores in the McGill pain questionnaire compared to ISCIP, indicative of a more intense chronic pain perceived by these subjects. In addition, the chronic pain below the level of spinal lesion, reported by CSCIP originated from a significantly larger body area than that of ISCIP. These results indicate that a critical level of chronic pain must be perceived in order to induce an elevation in acute pain threshold.

Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice.

The neuropeptide orphanin FQ (also known as nociceptin; OFQ/N) has been implicated in modulating stress-related behavior. OFQ/N was demonstrated to reverse stress-induced analgesia and possess anxiolytic-like activity after central administration. To further study physiological functions of OFQ/N, we have generated OFQ/N-deficient mice by targeted disruption of the OFQ/N gene. Homozygous mice display increased anxiety-like behavior when exposed to a novel and threatening environment. OFQ/N-null mice show elevated basal pain threshold but develop normal stress-induced analgesia. Interestingly, these mice show impaired adaptation to repeated stress when compared with wild-type mice, whereas their performance in spatial learning remained unaffected. Basal and poststress plasma corticosterone levels were found to be elevated in OFQ/N-deficient animals. Thus, OFQ/N appears to be crucially involved in the neurobiological regulation of stress-coping behavior and fear.

Elevated pain threshold in anorexia nervosa subjects

Background: Conflicting data have been published regarding pain threshold in subjects with anorexia nervosa (AN), with some studies indicating elevated pain threshold and others indicating normal thresholds. Previous research has indicated the presence of elevated pain threshold in eating disorder subjects with binge-eating behavior. Methods: In this study pressure pain detection thresholds (PDT) (assessed by a pressure analgesiometer) in binge-eating/purging and restricting subtypes of AN subjects were compared to control subjects. Results: PDT was elevated in AN compared to control subjects at baseline. There was no difference in PDT between the subgroups of AN subjects. Conclusions: The etiology of elevated PDT in AN subjects is most likely different from the etiology of elevated PDT in bulimia nervosa subjects.

A preliminary report on pain thresholds in bulimia nervosa during a bulimic episode

Subjects with bulimia nervosa (BN) have been shown to exhibit abnormal satiety responses. Short-term satiety is largely mediated by afferent vagal activity. Activation of afferent vagal fibers has also been found to stimulate a descending pain inhibitory pathway that leads to elevation in somatosensory pain thresholds. Therefore, the study of pain thresholds in BN subjects may lead to a better understanding of afferent vagal function in this disorder. In this preliminary study, pressure pain thresholds were assessed in nine subjects with BN on 3 consecutive days during a binge-eating and vomiting (B/V) episode, during a normal meal, and after an overnight fast. A significant time versus condition effect was found with a significant change in the pain threshold in BN subjects under the B/V condition only. These data are consistent with the hypothesis that vagal afferent activation by a B/V episode also activates the descending pain inhibitory pathway.

Electrotherapy for painrelief: does it work? A laboratory-based study to examine the analgesic effects of electrotherapy on cold-induced pain in healthy individuals

Interferential currents (IFC) are a type of transcutaneous electrical nerve stimulation(TENS) and are predominantly administered for the management of pain, however, there is little objective evidence to support their clinical effectiveness. This paper demonstrates the value of laboratory-based studies in the initial assessment of the analgesic effects of an electrotherapy and discusses the findings of a single blind placebo-controlled study which examined the analgesic effects of IFC on cold-induced pain in 40 healthy individuals. Subjects completed six cycles of the cold-induced pain test during which the time to pain threshold(s) and the self report of pain intensity and pain unpleasantness (0–10 cm Visual Analogue Scale) were recorded. Subjects were randomly allocated to receive either active IFC or sham IFC treatment during the third and fourth experimental cycles. Two-way repeated measures ANOVA were performed on the percentage change in each outcome measure from the pretreatment baseline for each subject. Results showed that IFC elevated pain threshold when compared to sham IFC during treatment but not post treatment. There were no differences between the IFC and sham treatment groups for the percentage change in pain intensity and unpleasantness ratings. It was concluded that IFC produced analgesic effects which were greater than those produced by sham IFC for pain threshold, but not for the pain intensity and unpleasantness ratings under the present experimental conditions. However, these effects only occurred when the stimulator was switched on. The clinical implications of these findings are discussed.

A double blind placebo controlled investigation into the analgesic effects of inferential currents (IFC) and transcutaneous electrical nerve stimulation (TENS) on cold-induced pain in healthy subjects

Transcutaneous electrical nerve stimulation (TENS) and interferential currents (IFC) are used by physiotherapists for the management of painful conditions. It is claimed that the analgesic profiles of TENS and IFC differ although no studies have directly compared the analgesic effects of the two modalities. The aim of this double blind placebo controlled study was to compare the analgesic effects of TENS and IFC on cold-induced pain in healthy volunteers. Twenty one subjects completed six cycles of the cold-induced pain test (two pre-treatment, two during treatment, and two post-treatment). During each cycle pain threshold was recorded as the time from immersion of the subject's hand in cold water to the first sensation of pain and pain intensity and unpleasantness ratings were recorded using visual analogue scales. Subjects received one of the following treatments during the two treatment cycles: IFC, TENS, or sham electrotherapy. IFC and TENS were delivered at a ''strong but comfortable'' intensity via two electrodes applied over the anterior aspect of the forearm. Sham electrotherapy was administered by a ''dummy'' stimulator with no current output. All stimulators were visually identical. Analysis of the results found that IFC and TENS significantly elevated pain threshold when compared to sham electrotherapy (P <. 05). There were no significant differences in the magnitude of the increase in pain threshold between IFC and TENS. No significant changes in pain intensity or unpleasantness ratings were found between the three treatment groups. We conclude that there were no differences in the analgesic effects of IFC and TENS under the present experimental conditions.

ANALGESIC AND ANTIPYRETIC ACTIONS OF ENANTIA CHLORANTHA EXTRACT IN SOME LABORATORY ANIMALS

Aqueous extract of the bark of Enantia chlorantha administered intraperitoneally (i.p) into healthy adult albino mice at does of 1.0 and 5.0g/kg resulted in elevation of pain threshold. The action of E. chlorantha was found to be about 20 times less potent than morphine. On the other hand, a dose if 15.0g/kg of the extract given orally to rabbits infected with Klebsiella sp was able to relieve the pyrogenic induced fever whereas no such effect was observed in the control group that was given ordinary water. Key Words: Enantia chlorantha, Anonaceae, malaria, fever, pain, Klesbsiella sp., mice and rabbits Nig. J. Nat. Prod. And Med. Vol.2 1998: 24-25

Spinal administration of adrenergic agents produces analgesia in amphibians

Direct intraspinal injection of the catecholamines epinephrine and norepinephrine, and the α-adrenergic agents dexmedetomidine and clonidine, produced a dose-dependent elevation of pain thresholds in the Northern grass frog, Rana pipiens. Significant analgesic effects were noted for at least 4 h. The analgesic effect of intraspinal dexmedetomidine or epinephrine was blocked by systemic pretreatment with the α 2-adrenoceptor antagonists, yohimbine and atipamezole, but not with the α 1-adrenoceptor antagonist, prazosin. Dose-response analyses showed that dexmedetomidine, epinephrine, norepinephrine had similar analgesic potencies, but clonidine was significantly less potent. Analgesia was observed without accompanying motor or sedative effects. These results suggest that α 2-adrenoceptor mechanisms which mediate analgesia may have evolved early in vertebrate evolution and that descending epinephrine-containing fibers in the amphibian nervous system may be the source of endogenous catecholamines regulating nociceptive sensitivity in the amphibian spinal cord.

Endogenous opioid peptide mediation of hypoalgesic response in long-term diabetic rats.

This study was designed to examine the role of endogenous opioid peptide mediation of elevated pain threshold in adult male Sprague-Dawley rats with long-term diabetes mellitus induced by streptozotocin (STZ). Diabetes resulted in a significant elevation in pain threshold as measured by the tail-flick and/or hotplate latency tests. The hypoalgesic response in diabetic rats to hotplate testing developed gradually over a 4-6 week period after a transient hyperalgesia during the first two weeks of diabetes. The elevation of pain threshold achieved peak level by the fourth week after STZ administration, and remained at that level throughout the experimental period (up to 13 weeks). This hypoalgesic state in diabetic animals is thought to be mediated by opioid receptors (i.e. mu and delta). The involvement of the mu receptor is supported by the effect of naltrexone on the STZ-diabetic rats; naltrexone significantly attenuated the increase in tail-flick and hotplate latencies, compared to that of the non-diabetic controls. Furthermore, the concentration of native (free) Met-enkephalin in the spinal cord of STZ-diabetic rats was about 5-fold higher than that of non-diabetic animals. Such high levels of Met-enkephalin suggest the involvement of delta opioid receptors in the hypoalgesic response observed in STZ-diabetic rats. Seven weeks of insulin treatment, initiated after development of the hypoalgesic response, normalized not only plasma glucose level and body weight of diabetic rats, but also returned their antinociceptive latency toward normal. The results of this study showed that long-term diabetes is associated with altered pain threshold and further support the hypothesis for endogenous opioid peptide mediation of hypoalgesia in chronically diabetic rats that can be prevented by insulin treatment.

Influence of selective nerve fiber blocks on argon laser-induced thermal pain in the human skin

Influence of selective nerve fiber blocks on cutaneous pain induced by short argon laser pulses was studied in healthy humans. The minimal energy per surface area needed to produce a pain sensation was lower with a larger stimulus surface indicating spatial summation. Both compression of the peripheral nerve innervating the stimulus site (A-fiber block) and prolonged topical treatment of the stimulus site with 1% capsaicin (a predominant block of nociceptive C-fibers) produced an elevation of the pain threshold. Prolonged capsaicin treatment produced significantly higher pain thresholds than the compression block. Magnitude of the pain threshold elevation induced by nerve blocks varied depending on the area of the stimulus surface. Especially following prolonged capsaicin treatment, pain threshold elevations tended to be smaller with the larger area of the stimulus surface suggesting an enhanced spatial summation effect. Tactile thresholds were significantly elevated only by the compression block. The results indicate that nociceptive C-fibers have a significant contribution to the threshold sensation of pain induced by argon laser. Moreover, following impairment of function in nociceptive C-fibers, the spatial summation of argon laser-induced pain tends to be enhanced.