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PubMed2000

Effect of diabetes on bradykinin-induced thermal hyperalgesia in mice.

To investigate the role of protein kinase C in the attenuation of bradykinin-induced thermal hyperalgesia in diabetic mice, we examined the effects of a protein kinase C activator or inhibitor on the i.t. bradykinin-induced hyperalgesia in diabetic and non-diabetic mice. Intrathecal injection of bradykinin caused a transient antinociceptive effect, which diminished within 30 min, and then produced a thermal hyperalgesia, which lasted about 120 min, in non-diabetic mice. Although the duration of the antinociceptive phase was longer in diabetic mice than in non-diabetic mice, the hyperalgesic response was not observed in diabetic mice. The bradykinin-induced hyperalgesia was dose-dependently and significantly enhanced by pretreatment with calphostin C (0.3 to 3 pmol, i.t.), a specific protein kinase C inhibitor, in diabetic mice. However, calphostin C (3 pmol, i.t.) had no significant effect on bradykinin-induced hyperalgesia in non-diabetic mice. On the other hand, pretreatment with phorbol-12, 13-dibutyrate (12.5 to 50 pmol, i.t.), a protein kinase C activator, significantly and dose-dependently reduced bradykinin-induced hyperalgesia in non-diabetic mice. However, phorbol-12, 13-dibutyrate (50 pmol, i.t. ) had no significant effect on bradykinin-induced hyperalgesia in diabetic mice. These results suggest that the change in bradykinin-induced thermal hyperalgesia in diabetic mice may be due, at least in part, to the modification of nociceptive transmission in the spinal cord by the activation of protein kinase C.

Animals↗
PubMed1997

Local treatment with the N-methyl-D-aspartate receptor antagonist ketamine, inhibit development of secondary hyperalgesia in man by a peripheral action.

Due to the recent discovery of peripheral N-methyl-D-aspartate (NMDA) (and other glutamate) receptors in animal studies, the NMDA receptor antagonist, ketamine (0.83 mg/ml, 6 ml) or saline was injected s.c. preinjury in 10 healthy volunteers, to study the effect on burn-induced primary and secondary hyperalgesia. On the saline treated leg, all subjects developed primary hyperalgesia and secondary hyperalgesia. On the contralateral leg treated with ketamine, there was a significant reduction of primary hyperalgesia and an inhibition of development of secondary hyperalgesia. In an experimental day 2, lidocaine temporarily blocked the development of primary and secondary hyperalgesia. When saline was injected in the contralateral leg treated with ketamine 1 week previously (n = 6), no zone of secondary hyperalgesia was developed. In contrast, subjects (n = 3) treated with ketamine 2 weeks before, reported development of secondary hyperalgesia following saline, a preliminary indication of a long-lasting peripheral action of ketamine.

Adult↗
PubMed2001

Non-noxious A fiber afferent input enhances capsaicin-induced mechanical hyperalgesia in the rat.

Intradermal injection of capsaicin induces primary hyperalgesia at the injection site and secondary hyperalgesia in the surrounding undamaged skin. The secondary hyperalgesia is thought to be due to central sensitization of the dorsal horn neurons while primary hyperalgesia is caused by sensitization of nociceptors in the damaged skin. In this study, we asked if additional non-noxious afferent input from the undamaged skin influences the already developed secondary hyperalgesia, which follows an intradermal injection of capsaicin. Capsaicin dissolved in olive oil was injected into the middle of the hind paw of male Sprague-Dawley rats (250-300 g) under gaseous anesthesia. This produced a decrease in the mechanical threshold at the base of the toes for hind limb withdrawals lasting for 1-2h, thus showing a short-lasting (hours) secondary hyperalgesia. When the capsaicin injection was immediately followed by repeated non-noxious mechanical stimuli or weak electrical stimuli (A fiber strength) applied to the area of secondary hyperalgesia (toes) for 30 min, the reduction of the mechanical threshold lasted longer than 24h. These results suggest that non-noxious A fiber afferent input can powerfully modulate central sensitization in the spinal dorsal horn, causing the duration of the secondary hyperalgesia to be greatly extended.

Animals↗
PubMed1998

Hyperalgesia and temporal summation of pain after heat injury in man.

Temporal summation of pain occurs when repeated stimuli become increasingly painful in spite of unchanged stimulus intensity. Summation can be quantified as the difference in pain between the first and the last stimulus in a train of stimuli. The aim of the study was to compare temporal summation of pain in normal skin with summation of pain in skin with primary and secondary hyperalgesia evoked by a heat injury. A heat injury was produced on the crus of 12 volunteers with a 50 x 25 mm thermode (47 degrees C, 7 min). Measurements were made before, and 0, 1, 2, and 4 h after the heat injury, in three areas: primary and secondary mechanical hyperalgesia induced by the heat injury, and in a mirror image of the injury on the opposite leg. Temporal summation of pain was induced by repeated electrical stimuli (five stimuli at 2 Hz) and assessed by visual analog scale (VAS). Primary hyperalgesia was evaluated by von Frey hairs and electrical stimuli, and the areas of secondary hyperalgesia with a rigid von Frey hair (314 mN). Significant primary (P < 0.000001) and secondary (P < 0.00006) mechanical hyperalgesia were evoked by the heat injury. The pain threshold to single electrical stimuli was reduced within the injury (P < 0.03), but not outside. The pain responses to single and repeated electrical stimuli were not significantly altered by the injury. Temporal summation of pain occurred in 418 stimulus trains out of 576 (73%), but no significant changes in summation developed in skin with primary or secondary mechanical hyperalgesia compared with normal skin (baseline measurements). Temporal summation at high stimulus intensities was more pronounced than at lower intensities (P < 0.0002). We found no correlation between either temporal summation and area of secondary hyperalgesia, or temporal summation and pain intensity during the induction of heat injury. We conclude that the development of primary and secondary mechanical hyperalgesia after heat injury in man was not associated with changes in temporal summation of painful electrical stimuli.

Adult↗
PubMed1998

Secondary hyperalgesia and perceptual wind-up following intradermal injection of capsaicin in humans.

Wind-up and secondary hyperalgesia both are related to central sensitization, but whereas the former is explained by homosynaptic facilitation, the latter is due to heterosynaptic facilitation. To investigate possible interactions between both types of facilitation, we tested for alterations of perceptual wind-up in the secondary hyperalgesic skin zone adjacent to a capsaicin injection with light touch (by a cotton wisp) and punctate stimuli (calibrated von Frey hairs and pin pricks). Temporal summation of pain sensation (perceptual wind-up) was only observed with a clearly noxious stimulus (pin prick) presented at a repetition frequency of 0.6 s(-1), but not 0.2 s(-1). Pain ratings to trains of pin pricks reached a plateau after 3-4 repetitions, which was 1.65 times the initial rating ('wind-up ratio'). Injection of capsaicin induced a tenderness to mechanical stimuli in adjacent uninjured skin (secondary hyperalgesia), including hyperalgesia to light touch (allodynia) and hyperalgesia to punctate stimuli. Hyperalgesia to punctate stimuli was characterized by a leftward shift of the stimulus response function, corresponding to a decrease in pain threshold and an increase of painfulness of suprathreshold stimuli by a factor of 3-4. After capsaicin, the difference between the ratings of the first and last stimuli of trains of pin pricks was increased, but the ratio was unchanged. This behavior is equivalent to an increase in effective stimulus intensity, and could be mimicked by increasing the pin prick force from 20 mN to 40 and 80 mN in normal skin. Thus, the leftward shift of the stimulus response function fully accounts for all alterations of pain sensitivity to punctate stimuli in the zone of secondary hyperalgesia. We conclude that when the gain of spinal transmission was changed in secondary hyperalgesia, the gain of wind-up remained unchanged. These findings indicate that secondary hyperalgesia (heterotopic facilitation) and wind-up of pain sensation (homotopic facilitation) are independent phenomena.

Adolescent↗
PubMed1998

Effects of antihyperalgesic drugs on experimentally induced hyperalgesia in man.

In a double-blind, cross-over study, ibuprofen (600 mg), a peripherally-acting selective kappa-opioid receptor agonist (7.5 mg), or placebo were given orally in experiments on healthy volunteers 1 h before assessment of pain thresholds to radiant heat and of pain ratings to controlled mechanical impact stimuli. Mechanical and thermal hyperalgesia had been induced 24 h before by irradiating skin patches on the ventral side of the upper leg. UVB irradiation induced mechanical and thermal hyperalgesia at radiation dosages of three times the minimal erythema dose. UVA irradiation resulted in an immediate erythema and a delayed tanning of the skin, however, no hyperalgesia was observed. For comparison another model of mechanical hyperalgesia was applied in the same experiments which has been previously proven sensitive to non-steroidal anti-inflammatory drugs (NSAIDs). In this model hyperalgesia was assessed, which develops during repetitive pinching of skin folds (pinch model). Ibuprofen significantly diminished heat and mechanical hyperalgesia induced by UVB, but had no effect on pain responses obtained from untreated skin. It also had an antihyperalgesic effect in the pinch stimulus paradigm. In contrast, the kappa-agonist showed no antihyperalgesic efficacy in the chosen models. It is concluded that the UVB model, as the pinch model, is suitable for establishing antihyperalgesic effects of NSAIDs, but probably not of kappa-receptor agonists, in healthy human volunteers. Compared to the pinch stimulus model, the UVB model offers additional advantages: (a) drugs may be tested after induction of the skin trauma by UV and this situation is more similar to the clinical use of antihyperalgesic drugs. (b) Since mechanical and thermal hyperalgesia is induced by UVB, drug effects can be tested upon both forms of hyperalgesia.

Adult↗
PubMed1999

Hyperalgesia due to nerve damage: role of nerve growth factor.

The hypothesis that nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) contribute to hyperalgesia resulting from nerve damage was tested in rats in which the sciatic nerve was partially transected on one side. Administration of antisera raised against NGF and BDNF relieved mechanical and thermal hyperalgesia in these animals. It has been suggested that NGF may elicit hyperalgesia by inducing mast cells to release algesic agents such as serotonin (5-HT). We found that degranulation of mast cells with compound 48/80 relieved mechanical and thermal hyperalgesia produced by nerve damage. We also found that local injection of the 5-HT2A and 5-HT3 receptor antagonists ketanserin and ICS 205-930 into the affected hind paw relieved mechanical hyperalgesia in a dose-dependent fashion. These findings support the idea that in this rat model of hyperalgesia due to peripheral nerve damage, NGF acts on mast cells to induce release of 5-HT, which sensitizes nociceptors. Hyperalgesia due to nerve injury and hyperalgesia due to inflammation may share some common features.

Animals↗
PubMed2000

Secondary hyperalgesia persists in capsaicin desensitized skin.

Several lines of evidence suggest that secondary hyperalgesia to punctate mechanical stimuli arises from central sensitization to the input from primary afferent nociceptors. Conventional C-fiber nociceptors respond to heat stimuli and yet heat hyperalgesia is absent in the region of secondary hyperalgesia. This evidence suggests that the central sensitization to nociceptor input does not involve heat sensitive nociceptors. To test this hypothesis, we investigated whether desensitization of heat sensitive nociceptors by topical application of capsaicin led to an alteration in the secondary hyperalgesia. Two 2x2 cm areas on the volar forearm, separated by 1 cm, were treated in 10 healthy volunteers. One of the areas was desensitized by treatment with 10% topical capsaicin (6 h/day for 2 days). The other site served as vehicle control. Hyperalgesia was produced 2 days later by an intradermal injection of capsaicin (50 microg, 10 microl) at a point midway between the two treatment areas. Secondary hyperalgesia to noxious mechanical stimuli was investigated by using a blade probe (32 and 64 g) attached to a computer-controlled mechanical stimulator. In the area of topical capsaicin treatment, there was a marked increase in heat pain threshold and decrease in heat pain ratings indicating a pronounced desensitization of heat sensitive nociceptors. However, touch threshold and pain to pinching stimuli were not significantly altered. The intradermal capsaicin injection led to the development of a similar degree of secondary hyperalgesia at both the vehicle and capsaicin treatment areas. These results indicate that capsaicin insensitive nociceptive afferents play a dominant role not only in normal mechanical pain but also in secondary hyperalgesia to noxious mechanical stimuli.

Administration, Topical↗
PubMed2000

Functional interplay between gelatinases and hyperalgesia in endotoxin-induced localized inflammatory pain.

The role of ECM-degrading proteinases in normal developmental processes and in pathological conditions is extensively studied. However, few reports describe the role ECM-degrading proteinases play in modulating hyperalgesia. The goal of this study is to describe the regulation of gelatinases during endotoxin mediated local inflammation, induced by intra plantar endotoxin (ET; 1.25 microg/50 microl) injection in Balb/c mice, and to correlate that with hyperalgesia. ET injections induced hyperalgesia, as determined by hot plate and paw pressure tests, which peaked by 24 h and recovered by 48 h post-injection. Contralateral paw of ET injected mice and saline injected paws in control mice elicited no hyperalgesia. Zymography showed that ET and saline injected paws elicited increased gelatinase activity by 9 h after injection. However, only the former maintained high levels of expression of a 90 kD gelatinase up to at least 96 h post ET injection, while in the latter gelatinase expression was down regulated by 24 h. Interestingly, the 90-kD gelatinase was upregulated in the contralateral paw of the ET-injected mice beyond 48 h post injection. Saline injection in that paw, during a time when gelatinases are upregulated, induced hyperalgesia. Intraperitoneal injection of either ZnCl(2) (100 microM), thymulin (5 microg/100 microl), or morphine (2 mg/kg/100 microl) reversed the ET-induced hyperalgesia and suppressed gelatinase activity. Furthermore, intraperitoneal injection of MPI, an ECM-degrading proteinase inhibitor, reversed ET induced hyperalgesia. Taken together, the above suggests that a functional interplay exists between gelatinase upregulation triggered by ET injections and hyperalgesia. The exact mechanism underlying such correlation remains to be determined.

Animals↗
PubMed2000

Age-related differences in the time course of capsaicin-induced hyperalgesia.

The effect of age on hyperalgesia, one of the most common signs of injury, has not been previously examined in humans. A psychophysical study was conducted in 10 young (26.9+/-4.6 years) and 10 older (79. 0+/-5.7 years) healthy volunteers to investigate the effect of age on the development of hyperalgesia induced by topical application of capsaicin (0.1 ml, 5 mg/ml). The capsaicin patch (diameter 2 cm) was applied for 1 h. The intensity of capsaicin-induced spontaneous sensation, mechanical pain threshold, area of flare, heat and punctate hyperalgesia were measured hourly for 3 h after the application. Older adults took a longer period to report first pain. There was no age effect on the magnitude of spontaneous sensation, flare size and area of heat hyperalgesia. The area of heat hyperalgesia rapidly decreased over time in both age groups. In marked contrast, the area of punctate hyperalgesia and associated reduction in the mechanical pain threshold were maintained in older adults over the entire 3 h test period, but resolved rapidly in young adults. We conclude that, given the same intensity of noxious stimulation, older adults display a similar magnitude of hyperalgesia as younger persons. However, once initiated, punctate hyperalgesia appears to resolve more slowly in older people. This finding may indicate age differences in the plasticity of spinal cord neurons following an acute injury.

Administration, Topical↗
PubMed2000

The alpha(2A) adrenoceptor and the sympathetic postganglionic neuron contribute to the development of neuropathic heat hyperalgesia in mice.

We have addressed the role of the sympathetic nervous system in the development and maintenance of neuropathic pain. Using a new neuropathic mouse model, we examined the development of hyperalgesia in transgenic mice lacking functional alpha(2A) adrenoceptors and in sympathectomized wild-type mice, to determine if sympathetic-sensory coupling generates hyperalgesia. The development of neuropathic heat hyperalgesia required the presence of both the alpha(2A) adrenoceptor and the sympathetic postganglionic neuron (SPGN), but the development of mechanical hyperalgesia did not require either the alpha(2A) adrenoceptor or the SPGN, indicating different mechanisms of sensitization. These results suggest that the development of neuropathic heat hyperalgesia, but not mechanical hyperalgesia, requires sympathetic-sensory coupling in the peripheral nervous system. Nerve injury enhanced the analgesic efficacy of the alpha(2) adrenoceptor agonist dexmedetomidine, and paradoxically also induced an analgesic response to alpha(2) adrenoceptor antagonists. The alpha(2) agonist-evoked analgesia to mechanical stimuli was mediated by activating central alpha(2A) adrenoceptors, possibly at the spinal level. The peripherally restricted alpha(2) antagonist L659,066 evoked analgesia for heat, but not for mechanical stimuli, findings which support the hypothesis that the peripheral alpha(2) adrenoceptor plays a role in both the development and the maintenance of neuropathic heat hyperalgesia. The alpha(2) antagonist-evoked analgesia for heat stimuli was mediated by blocking peripheral and probably central alpha(2) adrenoceptors, while the analgesia for mechanical stimuli was mediated by blocking central alpha(2A) adrenoceptors. Intradermal injections with an alpha(2) agonist or antagonist had no effect on nociceptive thresholds, indicating that sympathetic-sensory coupling at the level of the cutaneous nociceptor did not contribute to the maintenance of neuropathic hyperalgesia.

Adrenergic alpha-Agonists↗
PubMed2002

Heat hyperalgesia in humans: assessed by different stimulus temperature profiles.

The aim of the present study was to investigate the effect of the rate of temperature increase on the intensity of the evoked pain before and after hyperalgesia induced by topical capsaicin. Further, hyperalgesia to suprathreshold heat stimuli was investigated. Thirteen healthy volunteers were included in the experiment. All stimuli were applied in randomised order within the volar surface of both forearms using a computer-controlled contact stimulator. In one of the forearms, the effect of the rate of temperature change was investigated for 1.0, 5.0, and 8.0 degrees C/s reaching a peak temperature of 30.0, 33.0, 36.0, 39.0, and 42.0 degrees C in the primary hyperalgesic area and reaching a peak temperature of 33.0, 36.0, 39.0, 42.0, 45.0, 47.0, and 49.0 degrees C in the secondary hyperalgesic area before and after the induction of hyperalgesia. In the other forearm, the same procedure was repeated without capsaicin application as a control measurement. After the induction of hyperalgesia, the pain ratings were significantly higher in the arm treated with capsaicin compared with baseline for 36, 39, and 42 degrees C heating rates in the primary hyperalgesic area. The pain ratings were significantly higher with 1 degrees C/s heating rate compared with 5 and 8 degrees C/s for 36, 39, and 42 degrees C in the primary hyperalgesic area. Heat hyperalgesia was also observed within the secondary hyperalgesic area to pin-prick for stimulus temperatures of 45, 47, and 49 degrees C compared with the baseline measurements. Increased ratings were found for all three heating rates in the secondary hyperalgesic area. There were no heat hyperalgesia in the control arm. In conclusion, hyperalgesia to suprathreshold heat stimuli was observed in the secondary hyperalgesic area and C-fibres play an important role in the primary hyperalgesia to heat.

Adult↗
PubMed1997

Involvement of interleukin-1 beta, nerve growth factor and prostaglandin E2 in endotoxin-induced localized inflammatory hyperalgesia.

1. Intraplantar endotoxin (ET) injection (1.25 micrograms) into the hind paw of rats resulted in a localized inflammatory hyperalgesia, as assessed by paw pressure (PP), paw immersion (PI), tail flick (TF) and hot plate (HP) tests. 2. ET injection resulted in a significant elevation in the levels of interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF) in the injected foot as compared with the non-injected foot. This increase was attenuated by intraperitoneal injections of dexamethasone (200 and 400 micrograms kg-1) and to a lesser extent by indomethacin (2 and 8 mg kg-1). 3. The tripeptide Lys-D-Pro-Val, which is known to antagonize IL-1 beta and prostaglandin E2 (PGE2) reversed mechanical hyperalgesia, as assessed by the PP test, and reduced significantly thermal hyperalgesia, as assessed by the HP and TF tests. 4. IL-1ra reversed both mechanical (PP) and thermal (PI) nociceptive thresholds tested on the injected leg and significantly reduced thermal hyperalgesia, as assessed by the HP and TF tests. 5. A sheep, anti-mouse NGF antiserum reversed mechanical hyperalgesia (PP test) but had little or no effect on thermal hyperalgesia (PI, HP and TF tests). 6. Our results indicate the importance of IL-1 beta, NGF and prostaglandin E2 (PGE2) in the development of ET induced hyperalgesia and the possible existence of different mechanisms underlying thermal and mechanical as well as central and peripheral hyperalgesia.

Animals↗
PubMed1993

Time course of primary and secondary hyperalgesia after heat injury to the skin.

We have examined the time course of, and relationship between, primary and secondary hyperalgesia after thermal injury to the skin in humans. Burn injuries (15 x 25 mm rectangular thermode, 49 degrees C, 5 min) were produced in eight healthy, unmedicated male volunteers, on the medial side of the right calf, on two occasions at least 8 days apart. Heat pain detection thresholds (HPDT), heat pain tolerance (HPT), mechanical pain detection threshold (MPDT) and the intensity of burn-injury induced erythema (skin erythema index, SEI) were assessed inside the burn injury. HPT was assessed only in one study period. Areas of hyperalgesia to pinprick and brush were determined outside the injury. Assessments were made before and regularly for 72 h after the burn injury. There was a decrease in heat pain and mechanical thresholds, an increase in SEI inside the injury and development of mechanical hyperalgesia outside the injury. These alterations were consistent between the two examination days. The time course of the intensity of primary hyperalgesia was related closely to that of changes in area of secondary hyperalgesia, and hyperalgesia outside the injury did not outlast hyperalgesia inside the injury in any volunteer. These findings suggest post-injury development of secondary hyperalgesia to be a dynamic process, closely related in time to a peripheral nociceptive input, with reversal to normal when the peripheral lesion disappears. These observations may be relevant to the concept of "pre-emptive" analgesia.

Adult↗
PubMed1999

Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A-fibre nociceptor input.

Tissue injury induces enhanced pain sensation to light touch and punctate stimuli in adjacent, uninjured skin (secondary hyperalgesia). Whereas hyperalgesia to light touch (allodynia) is mediated by A-fibre low-threshold mechanoreceptors, hyperalgesia to punctate stimuli may be mediated by A- or C-fibre nociceptors. To disclose the relative contributions of A- and C-fibres to the hyperalgesia to punctate stimuli, the superficial radial nerve was blocked by pressure at the wrist in nine healthy subjects. Secondary hyperalgesia was induced by intradermal injection of 40 microg capsaicin, and pain sensitivity in adjacent skin was tested with 200 micron diameter probes (35-407 mN). The progress of conduction blockade was monitored by touch, cold, warm and first pain detection and by compound sensory nerve action potential. When A-fibre conduction was blocked completely but C-fibre conduction was fully intact, pricking pain to punctate stimuli was reduced by 75%, but burning pain to capsaicin injection remained unchanged. In normal skin without A-fibre blockade, pain ratings to the punctate probes increased significantly by a factor of two after adjacent capsaicin injection. In contrast, pain ratings to the punctate probes were not increased after capsaicin injection when A-fibre conduction was selectively blocked. However, hyperalgesia to punctate stimuli was detectable immediately after block release, when A-fibre conduction returned to normal. In conclusion, the pricking pain to punctate stimuli is predominantly mediated by A-fibre nociceptors. In secondary hyperalgesia, this pathway is heterosynaptically facilitated by conditioning C-fibre input. Thus, secondary hyperalgesia to punctate stimuli is induced by nociceptive C-fibre discharge but mediated by nociceptive A-fibres.

Adult↗
PubMed2004

Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome.

Pain sensitivity was assessed in 11 patients (age 60 +/- 10 years) with 'primary' restless leg syndrome (RLS) (disease duration 18 +/- 15 years) and 11 age- and gender-matched healthy control subjects. Stimulus-response functions for pricking pain were obtained with seven calibrated punctate mechanical stimulators activating Adelta-high threshold mechano-nociceptors. Stimuli at the foot were significantly more painful than at the hand in both patients and healthy control subjects both in the morning and evening. Generally, pin-prick pain ratings in RLS patients were significantly elevated, by a factor of 5.3 in the upper limb and by a factor of 6.4 in the lower limb indicating a significant generalized static hyperalgesia more pronounced in the lower limb. In contrast, pain to light touch (allodynia = dynamic mechanical hyperalgesia) as tested by a battery of three gentle tactile stimuli was never reported. Acute single-dose dopaminergic treatment with 100 mg levodopa + 25 mg benserazide, 90 min prior to the evening measurements, largely resolved patients' RLS symptoms, but had no effect on pin-prick pain. Static hyperalgesia to pin-prick, however, was significantly reversed (median reduction -74%) by long-term individually tailored dopaminergic treatment. Our study shows that patients with RLS exhibit a profound static mechanical hyperalgesia to pin-prick stimuli, but no dynamic mechanical hyperalgesia (allodynia). This type of hyperalgesia is probably mediated by central sensitization to Adelta-fibre high-threshold mechanoreceptor input, a hallmark sign of the hyperalgesia type of neuropathic pain. The reduction of hyperalgesia in RLS patients by long-term dopaminergic treatment suggests that the pathophysiology of RLS includes disturbed supraspinal pain modulation involving the basal ganglia and/or descending dopaminergic pathways.

Adult↗
PubMed2001

Systemic tizanidine hydrochloride (Zanaflex) relieves thermal hyperalgesia in rats with an experimental mononeuropathy.

UNLABELLED: We sought to determine whether tizanidine, an alpha2-agonist, relieved thermal hyperalgesia in rats with surgically induced neuropathic pain. We used a Sprague-Dawley rat model in which a chronic constriction of the sciatic nerve caused the rats to develop postural changes, mechanical allodynia, and thermal hyperalgesia. Thermal hyperalgesia was verified through paw withdrawal latency (PWL). PWL was tested before surgery, after surgery, and after injections with tizanidine (0.5, 1.0, or 2.0 mg/kg) or normal saline. Ambulatory and total movements were evaluated by placing the rats in activity cages. Thermal hyperalgesia was induced in all rats after surgery. Tizanidine, but not saline, caused a significant improvement in PWL (P < 0.05), with complete reversal of thermal hyperalgesia at all doses on postoperative Day 6. Rats who received tizanidine 2 mg/kg maintained complete reversal of thermal hyperalgesia through postoperative Day 9. Some sedation was observed with tizanidine 2 mg/kg, but not with smaller doses. We conclude that tizanidine effectively reversed thermal hyperalgesia in a rat model. IMPLICATIONS: This study was conducted to determine whether tizanidine could attenuate the thermal hyperalgesia that occurs in rats with surgically induced chronic constriction of the sciatic nerve. Tizanidine was effective in reducing sensitivity to heat, as measured by paw withdrawal latency, and did not cause sedation at smaller doses.

Adrenergic alpha-Agonists↗
PubMed1998

Effects of intrathecally administered lamotrigine, a glutamate release inhibitor, on short- and long-term models of hyperalgesia in rats.

BACKGROUND: Lamotrigine is a sodium channel blocker that inhibits the neuronal release of glutamate. Systemic administration of lamotrigine induces analgesia in short- and long-term models of hyperalgesia in rats. Considering the key role of N-methyl-D-aspartate receptors in the sensitization of dorsal horn neurons that leads to hyperalgesia, the author hypothesizes that intrathecally injected lamotrigine would be effective in reducing the hyperalgesia. METHODS: Short-term hyperalgesia was induced by unilateral intraplantar injection of prostaglandin E2. Long-term hyperalgesia was produced by treating rats with streptozotocin, which causes diabetic neuropathy and, in a different group of animals, by loose ligation of the sciatic nerve (chronic constriction injury). Hyperalgesia was assessed by measuring withdrawal reaction time after paw pressure, and analgesia was measured by the thermal tail-flick test. RESULTS: In the short-term model, intrathecally administered lamotrigine (12.5, 25.0, and 100.0 microg) produced a dose-dependent increase in the reaction time of the hyperalgesic paw. The highest dose that completely restored the reaction time to control levels (26-29 s) from the hyperalgesic levels (12-15 s) did not affect the reaction time of the normal contralateral paw. In the tail-flick test, a consistent effect could be observed only with doses of 200 microg, which caused transient motor impairment of the hind paws. In the long-term models of hyperalgesia, intrathecally administered lamotrigine produced a dose-dependent and long-lasting (24-48 h) antihyperalgesic effect. CONCLUSIONS: Intrathecally administered lamotrigine produced a spinal, dose-dependent, and long-lasting antihyperalgesic effect in short- and long-term neuropathic models of hyperalgesia.

Analgesics↗