Changes In Pain Sensitivity Research Articles

Neuronal Plasticity Associated with Burn Injury and Its Relevance for Perception and Management of Pain in Burn Patients

Through the introduction of the gate control theory and various subsequent works, Ronald Melzack has inspired many investigators worldwide to realize two important facts about pain. First, incoming pain messages are subject to both negative and positive modulation, which significantly affect its perception. Second, the progression of knowledge about the basic mechanisms underlying persistent and chronic pain is critically dependent on the increased understanding of the complexity of the symptoms experienced by pain patients. The present paper examines these two very important issues in an effort to understand better the mechanisms that underlie the pain suffered by burn patients. The physiological responses to burn injury involve many different mediators and mechanisms, all of which contribute to pain perception and development of neuronal plasticity underlying short and long term changes in pain sensitivity. While experimental burn injuries in humans and animals are typically well controlled and mild, in burn victims, the severity is much more variable, and clinical care involves repeated traumas and manipulations of the injured sites. Recurrent inputs from damaged and redamaged tissue impinge on a nervous system that becomes an active participant in the initiation of changes in sensory perception and maintenance of long term sensory disturbances. Recently acquired experimental evidence on postburn hyperalgesia, central hyperexcitability and changes in opioid sensitivity provides strong support that burn patients need an analgesic approach aimed at preventing or reducing the ′neural′ memory of pain, including the use of more than one treatment modality. Burn injuries offer a unique opportunity to combine experimental and clinical research to understand pain mechanisms better. Over the years, Ronald Melzack has insisted that one of the most laudable enterprises in research is to span the gap between these two often separate worlds.

Corticotropin-releasing-hormone lacks analgesic properties: an experimental study in humans, using non-inflammatory pain

The antinociceptive potency of corticotropin-releasing-hormone (CRH) has been established in several animal studies in which both central and peripheral sites of action were considered. However, there have not yet been any experimental trials, besides one attempt using clinical dental pain demonstrating the potential analgesic properties of CRH in humans. For this reason, we studied the effect of CRH on experimental heat pain sensitivity in 18 healthy men, using a double-blind, cross-over and placebo-controlled design. A dose of 100 μg (i.v.) was chosen because of its well-known neuroendocrine effects in humans. The pain parameters assessed were, visual analog scale (VAS) ratings for pain intensity and pain unpleasantness, pain thresholds and scores for discrimination ability. To differentiate between a direct analgesic effect of CRH and indirect effects via evoked hormonal responses in the hypothalamic-pituitary-adrenocortical (HPA) system ( β-endorphin, ACTH, cortisol), CRH was applied with and without a pre-treatment with dexamethasone. In neither of the two conditions was there any systematic change in our pain parameters. This failure to find any evidence suggesting an analgesic action of CRH or of the subsequent hormones of the HPA system was obtained despite the fact that CRH produced clear neuroendocrine responses such as increases in the plasma concentration of β-endorphin and cortisol. It is unclear whether the lack of analgesic action of CRH is due to its non-existence in humans, due to the use of a pain model which does not assess minute changes in pain sensitivity and does not trigger substantial inflammatory responses, or due to an insufficient dose of CRH.

Mental stress test-induced changes in pain sensitivity and haemodynamic variables

Mental stress test-induced changes in pain sensitivity and haemodynamic variables

Clinical and electrophysiological assessment of inferior alveolar nerve function after lateral nerve transposition.

Inferior alveolar nerve (IAN) transposition surgery may cause some degree of sensory impairment. Accurate and reproducible tests are mandatory to assess IAN conduction capacity following nerve transposition. In this study subjective (heat, pain and tactile-discriminative tests) and objective (electrophysiological) assessments were performed in 10 patients receiving IAN transposition (bilaterally in 8 cases) in order to evaluate any impairment of the involved nerves one year post-operatively. All patients reported a tingling, well-tolerated sensation in the areas supplied by the mental nerve with no anaesthesia or burning paresthesia. Tactile discrimination was affected the most (all but 1 patient). No action potential was recorded in 4 patients' sides (23.5%); 12 sides showed a decreased nerve conduction velocity (NCV) (70.5%) and 1 side normal NCV values (6%). There was no significant difference in NCV decrease between partial and total transposition sides, if examined separately. Nerve conduction findings were related 2-point discrimination scores, but not to changes in pain and heat sensitivity. These findings show that lateral nerve transposition, though resulting in a high percentage of minor IAN injuries, as determined by electrophysiological testing, provides a viable surgical procedure to allow implant placement in the posterior mandible without causing severe sensory complaints. Considering ethical and forensic implications, patients should be fully informed that a certain degree of nerve injury might be expected to occur from the procedure. Electrophysiological evaluation is a reliable way to assess the degree of IAN dysfunction, especially if combined with a clinical examination. Intraoperative monitoring of IAN conduction might help identify the pathogenetic mechanisms of nerve injury and the surgical steps that are most likely to harm nerve integrity.

Circadian Rhythm of Pain in Male Mice

1. Circadian rhythm of pain in response to the thermal stimuli was assessed in male mice. 2. The hot-plate method was used. Response latencies were measured every 2 hours and showed a sinusoidal rhythm. 3. Minimal latencies were observed at 10 and 20 h, the highest were obtained at 12 and 4 hours. 4. The circadian changes in pain sensitivity may play an important role in many experiments on stress and post-stress analgesia as well as on susceptibility to pharmacological agents.

Menstrual cycle modulation of tender points

Changes in pain sensitivity throughout the menstrual cycle were assessed in 36 normally menstruating women and 30 users of oral contraceptives. Pain sensitivity was measured with palpation of rheumatological tender points and with pressure dolorimetry. The number of tender points identified by palpation was greater in the follicular (postmenstrual) phase of the cycle as compared to the luteal (intermenstrual) phase in normally cycling women but not in users of oral contraceptives. These findings are related to previously described physiological and psychological features of the menstrual cycle, with particular emphasis on the role of hormonal events in modulating pain perception, particularly in musculoskeletal disorders such as fibromyalgia.

Antinociception following opioid stimulation of the basolateral amygdala is expressed through the periaqueductal gray and rostral ventromedial medulla

The amygdala, periaqueductal gray (PAG), and rostral ventromedial medulla (RVM) are critical for the expression of some forms of stress-related changes in pain sensitivity. In barbiturate anesthetized rats, microinjection of agonists for the μ opioid receptor into the amygdala results in inhibition of the tail flick (TF) reflex evoked by radiant heat. We tested the idea that TF inhibition following opioid stimulation of the amygdala is expressed through a serial circuit which includes the PAG and RVM. Rats were anesthetized and prepared for microinjection of DAMGO (0.5 μg/0.25 μl) into the basolateral amygdala (BLA) and lidocaine HCl (2.5%/0.4–0.5 μl) into either the ventrolateral PAG or RVM. Lidocaine did not significantly alter baseline values for TF latency or TF amplitude. When injected into the PAG prior to DAMGO application in the BLA, lidocaine significantly attenuated DAMGO-induced antinociception for the entire 40 min testing session. Similar treatment in the RVM also resulted in an attenuation of antinociception although rats showed significant recovery of TF inhibition by 40 min after lidocaine injection. Since acute injection of lidocaine into the RVM also affected baseline heart rate, separate animals were prepared with small electrolytic lesions placed in the RVM. Chronic RVM lesions also blocked TF inhibition produced by amygdala stimulation but did not affect heart rate. These results, when taken together with similar findings in awake behaving animals, suggest that a neural circuit which includes the amygdala, PAG, and RVM is responsible for the expression of several forms of hypoalgesia in the rat.

Ischemic but not thermal pain sensitivity varies across the menstrual cycle.

Findings from both animal and human research suggest that pain sensitivity changes across the menstrual cycle; however, among humans the nature of these menstrual cycle effects remains unclear. The present study used a repeated-measures design to evaluate changes in thermal and ischemic pain responses during three phases of the menstrual cycle, midfollicular (postmenstrual), ovulatory, and mid-to-late luteal (premenstrual), in 11 healthy women. The cycle phase during which subjects began their participation was determined randomly. Plasma levels of estrogen, progesterone, luteinizing hormone (LH), testosterone, and beta-endorphin were determined at each experimental session. Participants also completed a daily diary of physical and emotional symptoms for two complete menstrual cycles before the experimental sessions. The results indicated that women showed less ischemic pain sensitivity during the midfollicular compared with the ovulatory and mid-to-late luteal phases, but thermal pain responses did not vary significantly across menstrual cycle phases. Physical and emotional symptoms were minimal and did not change significantly across the menstrual cycle. These findings indicate greater ischemic but not thermal pain sensitivity among women after the midcycle LH surge. The practical relevance and potential mechanisms of these findings are discussed.

Reunion of Separated Sibling Mice: Neurobiological and Behavioral Aspects

Outbred albino NMRI male mice encountering a brother in adulthood, after a long period of separation, show an opioid-dependent increase in pain threshold. Unrelated and unfamiliar males show no similar changes in pain sensitivity. This study investigates which kind of stimuli from the partner may be responsible for such a modification at the neural level. The tail-flick test is used as a measure of pain sensitivity. Exposure to the scent of the brother's home cage, as well as exposure to visual, olfactory and auditory stimuli and partial physical contact with the related male, are not sufficient to induce changes in nociception. Physical affiliative contact between males is higher in sib than in nonsib pairs, and a positive correlation exists in sib pairs between huddling behavior and pain sensitivity at the end of a 2-h social session. Siblings injected with naloxone, an opioid receptor blocker, show a decrease in social behaviors involving physical contact. These results suggest that physical affiliative contact between sibling mice may be responsible for the enhancement of nociceptive threshold.

Neurobehavioral effects of Δ9-THC and cannabinoid (CB1) receptor gene expression in mice

The differential sensitivity following the administration of Δ 9-THC to 3 mouse strains, C57BL/6, DBA/2 and ICR mice, indicated that some of the neurobehavioral changes may be attributable to genetic differences. The objective of this study was to determine the extent to which the cannabinoid (CB1) receptor is involved in the observed behavioral changes following Δ 9-THC administration. This objective was addressed by experiments using: (1) DNA-PCR and reverse PCR; (2) systemic administration of Δ 9-THC, and; (3) intracerebral microinjection of Δ 9-THC. The site specificity of action of Δ 9-THC in the brain was determined using stereotaxic surgical approaches. The intracerebral microinjection of Δ 9-THC into the nucleus accumbens was found to induce catalepsy, while injection of Δ 9-THC into the central nucleus of amygdala resulted in the production of an anxiogenic-like response. Although the DNA-PCR data indicated that the CB1 gene appeared to be identical and intronless in all 3 mouse strains, the reverse PCR data showed two additional distinct CB1 mRNAs in the C57BL/6 mouse which also differed in pain sensitivity and rectal temperature changes following the administration of Δ 9-THC. It is suggested that the diverse neurobehavioral alterations induced by Δ 9-THC may not be mediated solely by the CB1 receptors in the brain and that the CB1 genes may not be uniform in the mouse strains.

Perinatal exposure toΔ 9-tetrahydrocannabinol (Δ 9-THC) leads to changes in opioid-related behavioral patterns in rats

Perinatal exposure to cannabinoids has been shown to elicit central nervous system impairment in rodents. This includes changes in monoaminergic and neuropeptidergic activities. We have examined the effect of perinatal exposure toΔ 9-tetrahydrocannabinol (Δ 9-THC) on sensitivity to radiant heat in both male and female rats on days 24, 50 and 70 after birth. Animals used in this experiment were born of mothers that receivedΔ 9-THC (5 mg/kg; p.o.) daily from day 5 of pregnancy until day 24 after offspring birth.Δ 9-THC perinatally treated males, but not females, showed higher baseline tail-flick values than controls on days 24 and 50 (Day 24, controls: 3.88 ± 0.18 s;Δ 9-THC group: 4.51 ± 0.18 s; Day 50, controls: 3.16 ± 0.17 s;Δ 9-THC group: 4.38 ± 0.38 s). In addition, adult males were found to be tolerant to the analgesic effect of morphine (5 mg/kg; i.p.; % analgesia: controls 71.75 ± 10.20;Δ 9-THC 35.5 ± 10.59). Moreover, recently weaned pups that received 5 mg/kg of naloxone (i.p.) developed an opioid-like withdrawal syndrome. Taken together all these results suggest that perinatal treatment withΔ 9-THC may alter the functionality of the endogenous opioid system, including changes in pain sensitivity.

Behavioral and developmental changes associated with prenatal opiate receptor blockade

Pregnant Long-Evans hooded rats were dosed with 1, 5, or 10 mg/kg per day naloxone from gestational day 7 (GD7) through GD20. The control groups included both uninjected animals and injected animals pairfed to the 10-mg dose animals. At birth, all litters were culled to four males and four females, and fostered to undosed surrogate dams. Prenatal naloxone exposure produced changes in body weight development, pain sensitivity, and motor behavior in the offspring. Five and 10 mg/kg naloxone increased adult body weights in females only, as did the pairfeeding condition. The 10 mg/kg naloxone altered pain sensitivity (in males only) as measured by the tail flick test. Animals in the 1 mg/kg dose condition habituated more rapidly than uninjected (UN) subjects in the open field, and showed less activity than UNs as they matured. Bar pressing rates were reduced in the 10 mg/kg dose males in a visual discrimination task, while 10 mg/kg males and females showed reduced bar pressing rates on differential reinforcement of low rates of responding (DRL). These findings confirm that prenatal exposure to naloxone alters some aspects of neurobehavioral development in the rat, and are consistent with the hypothesis that 1 mg/kg prenatally may increase opiate function in offspring, while 10 mg/kg prenatally may decrease opiate functioning in the offspring.

Changes in CNS neuropeptide FF-like material, pain sensitivity, and opiate dependence following chronic morphine treatment.

Tolerance and dependence to opiates may be an adaptive process that limits excessive effects of morphine on the CNS. Because no consistent opiate receptor reduction in chronically treated rats seems to underlie the hyposensitivity to morphine, an alternative hypothesis has postulated a role of "antiopioid" peptides. It is possible to speculate that the administration of morphine stimulates antiopioid systems such as neuropeptide FF (NPFF), as part of an homeostatic mechanism contributing to the development of tolerance. To test this hypothesis, pain sensitivity, opiate dependence, and CNS NPFF-IR levels were estimated at different times after implantation of morphine pellets (2 x 75 mg; NIDA). Three hours after morphine pellet treatment the analgesic effect was maximum and it decreased rapidly during the following 12 h. Naloxone-precipitated withdrawal syndrome was detected as soon as 3 h after morphine pellet implantation and was maximal after 24 h. NPFF-IR levels were measured in the spinal cord, brain stem, and hypothalamus. A significant decrease of NPFF-IR was observed 1 h after morphine pellet implantation (-25% to -45% depending on the structures) followed by a drastic increase of NPFF-IR levels (+60 to +140%) between 3 and 6 h. NPFF-IR levels rapidly returned to baseline after 24-36 h. It is suggested that the activity of these NPFF-IR neurones may increase gradually as a consequence of the continuous stimulation of opiate receptors and be part of an adaptive process that is able to counteract morphine effects and to induce dependence and tolerance to the analgesic effects of opiates.

Altered heat pain thresholds and cerebral event-related potentials following painful CO 2 laser stimulation in subjects with fibromyalgia syndrome

A decrease in mechanical pressure pain thresholds, particularly over pre-designated tender points, is one of the defining characteristics of fibromyalgia syndrome (FS); however, changes in thermal pain sensitivity have not been investigated. The present study examined heat pain thresholds and cerebral event-related potentials following CO 2 laser stimulation in 10 subjects with FS and 10 age-matched control volunteers. The results indicate that patients with FS exhibit a significant reduction in heat pain threshold when tested on the dorsal surface of the hand. In accordance with previous research, we also found a decrease in mechanical pain threshold over pre-designated tender points and at control sites as well as a significantly larger mechanically induced neurogenic flare response. These measures were highly correlated with thermal pain threshold even though different anatomical sites were stimulated. Hence, it seems likely that FS patients display a multimodal change in pain sensitivity which is generalized rather than anatomically restricted. Patients with FS also displayed a significant increase in the peak-to-peak amplitude of the cerebral potential evoked by CO 2 laser stimulation at pain threshold intensity and 1.5 times pain threshold intensity. These findings suggest a greater activation of central nervous system (CNS) pathways following noxious input. Putative explanations for the increased CNS response are discussed, including mechanisms of peripheral nociceptor sensitization, altered CNS function and the role of psychological factors.

Nursing-induced changes in pain sensitivity, prolactin, and somatotropin in the pig

Suckling by piglets led to increases in prolactin and somatotropin in the sow. Failed nursing attemps, which did not result in milk ejection, also led to elevations of prolactin and somatotropin, suggesting that massage of the udder is sufficient and milk ejection is not necessary for these hormonal changes to occur. Prior treatment with the opioid antagonist, naloxone, blocked the nursing-induced increases in prolactin and somatotropin. Tail-flick latencies of the sows were significantly elevated after a nursing, suggesting reduced pain sensitivity. This was blocked by naloxone, suggesting that nursing directly increases endogenous opioid activity. Removing piglets for 2 h led to a drop in prolactin and somatotropin. When the piglets were returned, the nursing-induced increase in prolactin and somatotropin tended to be higher than following a normal nursing interval (1 h). However, prolactin concentrations remained at a significantly lower level following the extended nursing interval. A reduction in nursing frequency seems likely to lead to reduced prolactin levels and altered patterns of somatotropin secretion.

Changes in pain sensitivity induced by raised atmospheric pressure

Changes in pain sensitivity induced by raised atmospheric pressure

Changes in Met- and Leu-enkephalin concentration in brain structures of rats with burn shock

The role of genetic and seasonal factors in stress-induced changes of pain sensitivity, evaluated by latency in hot plate test was studied. Significant interstrain differences in restriction effect on pain sensitivity was established. Analgesia, hyperalgesia or lack of influence on pain sensitivity in mice of different strains was observed in response to emotional stress. Interstrain differences in seasonal variance of stress-induced changes in pain sensitivity were shown. It is suggested that changes in pain sensitivity of mice after restriction are season-dependent and controlled by hereditary mechanisms.

Do enkephalins in basal ganglia mediate a physiological motor rest mechanism?

Thermal injury (30-s immersion in water at 62 degrees C) of one hind limb of rats caused a gradual withdrawal of the limb from use, such that after 1 week 50% of the animals walked on three legs. At 24 h following thermal lesion and at a time when the lesioned paw was still used for walking there was a reduction in met- and leu-enkephalin content in the periaqueductal grey (PAG) and bilateral reduction in leu-enkephalin content of the globus pallidus, but no change in enkephalin levels in caudate-putamen. One week following the lesion, animals exhibiting complete withdrawal of the injured limb, showed bilateral reduction of met- and leu-enkephalin content of PAG. Both met- and leu-enkephalin content in caudate-putamen. In each case the change was more marked in basal ganglia areas contralateral to the lesion. In animals lesioned 1 week previously and which did not use the injured limb, there was no change in the monoamine (or metabolite) content of caudate-putamen or in the spontaneous or potassium-evoked release of 3H-dopamine from strial slices. Thermal injury did not cause any general change in pain sensitivity and the time of change in pain threshold in the injured limb did not parallel the withdrawal of the affected limb from walking. The results suggest that after a thermal limb lesion, delayed changes in basal ganglia enkephalin content may be important in withdrawing the injured limb from the normal pattern of locomotion. Basal ganglia enkephalins may be involved in a physiological rest mechanism, which allows healing of the affected part.

Aggressive behavior inhibition by serotonin and quipazine injected into the amygdala in the rat

The effects on aggressive behavior, open-field activity, and pain threshold of bilateral microinjections of serotonin (20 micrograms) and quipazine (20 micrograms), the direct serotonergic receptor agonist, into the cortico-medial amygdala were investigated in Wistar rats. Both drugs significantly prolonged the attack latency in isolated killer rats (predatory aggression model), and suppressed the incidence of aggressive postures/attacks in shock-induced fighting test (affective aggression). The only difference in the open-field behavior was the lower number of central square entries in drug-treated compared to saline-injected rats. None of the substances produced any significant change in jump threshold. It is concluded that stimulation of serotonin receptors within the amygdala produces inhibition of affective and muricidal behavior in isolated rats. The effect does not seem to be dependent on changes in general activity and pain sensitivity.

Comparison of the effects of ventral medullary lesions on systemic and microinjection morphine analgesia

The effects of electrolytic lesions of the nucleus raphe magnus (NRM), nucleus reticularis paragigantocellularis (PGC) and nucleus raphe alatus (NRA) on analgesia elicited in the rat from systemic morphine and morphine microinjection into the periaqueductal gray (PAG) were evaluated using the tail flick test. No consistent change in baseline pain sensitivity was observed following lesions of the NRM, PGC or NRA. To determine the effect of ventral medullary lesions on systemic porphine analgesia, pain sensitivity was assessed prior to and 40 min after 6 mg/kg morphine administration (i.p.) at 2 days preceding lesioning and 5, 12 and 19 days post-lesion. NRM and PGC lesions produced only slight reductions in analgesia at 5 days after surgery. It was observed that large NRM, large PGC, and NRA lesions significantly attenuated analgesia evaluated at 12 days post-lesion. Smaller lesions confined within the NRM or PGC were reliably less effective than the larger lesions in reducing analgesia. In a subsequent study, 5 μg morphine in 0.5 μl saline was microinjected into the ventral PAG at the level of the dorsal raphe. Identical testing procedures were used and the analgesia was assessed at 2 days before lesioning and 5 and 12 days post-lesion. In contrast to the previous study, large NRM lesions abolished analgesia as early as 5 days following lesioning. Small NRM lesions were less effective and PGC lesions were generally ineffective in attenuating analgesia induced by morphine microinjection. We conclude that the NRA may act as a functional unit in the mediation of systemic morphine analgesia. In contrast, analgesia elicited from intracerebral (PAG) morphine microinjection is mediated via the NRM.