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PubMed2005

Effects of pertussis toxin on electroacupuncture-produced anti-hyperalgesia in inflamed rats.

Our previous study showed that electroacupuncture (EA) significantly attenuated hyperalgesia in an animal model of persistent inflammatory pain. The present study was designed to show if Gi/o protein is involved in EA-produced anti-hyperalgesia. Spinal Gi/o-protein function was destroyed by intrathecal pretreatment with pertussis toxin (PTX). Seven days after the placement of an intrathecal PE-10 tube, PTX was injected into the intrathecal space of the lumbar spinal cord of rats. Seven days after PTX, complete Freund's adjuvant (CFA) was injected into the plantar surface of one hind paw of the rat to induce hyperalgesia in the injected paw. EA treatment was given at acupoint GB30 immediately post-CFA and then hyperalgesia was assessed by measuring the degree of decreased paw withdrawal latency (PWL) to a noxious thermal stimulus. The results showed that PTX pretreatment prevented EA-produced anti-hyperalgesia in the CFA inflammatory pain model but did not affect either baseline pain threshold or CFA-induced hyperalgesia. The data suggest that EA-produced anti-hyperalgesia is mediated by PTX-sensitive Gi/o proteins and the relevant signaling pathways.

Animals↗
PubMed2004

Attenuation of mechanical but not thermal hyperalgesia by electroacupuncture with the involvement of opioids in rat model of chronic inflammatory pain.

Opioid peptides have been proven effective in reducing the sign of hyperalgesia associated with inflammation. Electroacupuncture (EA) produces antinociception via release of endogenous opioid peptides in normal rats. Moreover, intrathecal injection of dynorphin has antinociceptive effect in rats. The present study was designed to examine whether EA has effect on the thermal and mechanical hyperalgesia in rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. The results are the following: (1) single session of 100Hz EA (0.5-1.0-1.5 mA, 10 min for each intensity) at both Zusanli (ST 36) and Sanyinjiao acupoints (SP 6) significantly increased mechanical withdrawal threshold determined by von Frey filaments but not with thermal withdrawal latency that is determined by hot plate (52 +/- 0.2 degrees C); (2) 100 Hz EA applied twice a week for 4 weeks and showed a significant decrease in the mechanical hyperalgesia at the third and fourth week, with no effect on thermal hyperalgesia; (3) naloxone (20 mg kg(-1)) had the ability to reverse the inhibition of the mechanical hyperalgesia produced by a single session of EA. In conclusion, the present results indicate that a single or repetitive EA could reduce mechanical hyperalgesia, but not thermal hyperalgesia, in CFA-inflammatory pain rats, and the opioid system might be involved in these effects.

Animals↗
PubMed2004

A new rodent model of hind limb penetrating wound injury characterized by continuous primary and secondary hyperalgesia.

UNLABELLED: This article reports the development of a new hind limb pain model in which an incisional stab wound is placed on the front and back of the calf, causing both superficial and deep tissue injury. The injury causes primary mechanical hyperalgesia on the calf and secondary hind paw hyperalgesia, which served as the focus of the present study. Animals with unilateral stab wounds showed a significant increase in percent paw withdrawal (secondary mechanical hyperalgesia, reversed by morphine administration) from 2 to 48 hours after surgery, but no evidence of thermal hyperalgesia. In contrast, animals with bilateral leg injuries showed bilateral secondary mechanical and thermal hyperalgesia. Rats with unilateral leg incisional stab wounds showed a significant decrease in cage activity in both the horizontal and vertical directions, monitored by using a novel activity box approach, as compared to their 24-hour baseline levels or to the activity of naïve animals. Analysis of spinal cord Fos labeling demonstrated that calf injury significantly increased Fos expression in laminae I to VI of the L3-L5 cord segments. The data indicate that this model might be useful for evaluation of the mechanisms underlying penetrating injury-induced primary and secondary hyperalgesia or for testing the effect of analgesics on hyperalgesia induced by such injury. PERSPECTIVE: Stab wounds and other types of penetrating wounds routinely encountered in emergency rooms and clinics are accompanied by pain associated with superficial and deep tissue injury. Here we present a rodent stab wound model that affords an opportunity to study the mechanisms of pain associated with traumatic injury.

Analgesics, Opioid↗
PubMed2006

Time course and dose-dependence of nerve growth factor-induced secondary hyperalgesia in the mouse.

UNLABELLED: Administration of the neurotrophin nerve growth factor (NGF) to rats and humans has been shown to induce both thermal and mechanical hyperalgesia and is used as a model of inflammatory pain. Here we describe a mouse model of secondary hyperalgesia after NGF application. NGF was injected into the biceps femoris muscle unilaterally, and at various intervals afterwards the electromyographic (EMG) activity from the same muscle was recorded in response to mechanical von Frey hair stimulation of the plantar surface of the hind paw in isoflurane-anesthetized mice. Secondary cutaneous hyperalgesia in the hind paw reached a peak 60 minutes after injection and returned to baseline levels after an additional 60 minutes. This was followed by a second increase in EMG magnitude at 24 hours after injection that was still present after 5 days. The effects of NGF were dose-dependent, and a dose of 2 microg/g NGF had the maximal observed effect. No increase in EMG magnitude occurred on the untreated side. This study describes a quantitative mouse model of prolonged secondary cutaneous hyperalgesia after NGF-induced muscle inflammation that can be used for genetic manipulations of putative central molecular pathways that underlie secondary hyperalgesia. PERSPECTIVE: This study describes the development of a novel model of NGF-induced secondary hyperalgesia. The development of this model will allow further investigations into the processes that underlie the development of secondary hyperalgesia and pain associated with the musculature.

Animals↗
PubMed2004

Prevention by celecoxib of secondary hyperalgesia induced by formalin in rats.

Administration of formalin in rat paws results in stimulation of nociceptive pathways, which leads to an increase in the excitability of neurons present in dorsal horn. This increased neuron excitability, described as central sensitization, may result in development of inflammatory pain at a distant site of injury application, known as secondary hyperalgesia. The aim of the present study was to verify whether formalin injection in rat paws would lead to secondary hyperalgesia development, as measured by the tail-flick test. We also aimed to investigate whether celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, would affect secondary hyperalgesia. Formalin injected into the rat paws significantly reduced the latency for a flick response in the rat tail, which characterized development of secondary hyperalgesia. In addition, formalin-induced secondary hyperalgesia was locally prevented by pre-but not post-celecoxib treatment. However, celecoxib administered spinally inhibited formalin-induced secondary hyperalgesia, either administered previously or following formalin. In contrast, piroxicam, an unspecific COX inhibitor which displays an increased selectivity towards COX-1, only prevented secondary hyperalgesia to formalin at a high dose following spinal administration. Taken together, these results suggest that COX-2 plays an important role both in the central and in the peripheral nerve sensitization following formalin administration in rat paws. They also suggested that once central sensitization starts it can no longer be blocked by a specific COX-2 inhibitor administered locally. Notwithstanding, spinal administration of a specific COX-2 inhibitor still blocks ongoing sensitization and prevents maintenance of central sensitization.

Analysis of Variance↗
PubMed2006

Delayed L-DOPA-induced hyperalgesia.

Previously we reported on L-DOPA's antinociceptive effect on substance P-induced nociceptive behaviors in mice [Shimizu T, Iwata S, Morioka H, Masuyama T, Fukuda T, Nomoto M. Antinociceptive mechanism of L-DOPA. Pain 2004;110;246-9.]. Since significant hyperalgesia was noted following antinociception, our study was designed to investigate the mechanism of this hyperalgesia. Nociceptive behaviors were enhanced 2 h after L-DOPA administration. L-DOPA induced hyperalgesia occurred after conversion to dopamine because co-administration of benserazide, a DOPA decarboxylase inhibitor, completely abolished the L-DOPA-induced hyperalgesia. The D2 receptor agonist, quinpirole, depressed these behaviors entirely, while the D1 antagonist, SCH23390, inhibited the enhancement of these behaviors by L-DOPA. The D2 receptor antagonist, sulpiride, which induced hyperalgesia of the substance P-induced behaviors in naive mice, did not have any effects on L-DOPA-induced hyperalgesia. Spinal cord dopamine content increased rapidly after L-DOPA administration, exhibiting levels 100 times greater than baseline, and then returned to control after 1 h. These results suggested that the dopaminergic inhibitory system for pain sensation was temporarily impaired by excess amounts of exogenous dopamine that were derived from L-DOPA and both D1 and D2 receptors were involved in L-DOPA-induced hyperalgesia.

Animals↗
PubMed2004

Reversal of ongoing thermal hyperalgesia in mice by a recombinant herpesvirus that encodes human preproenkephalin.

Herpesvirus-mediated transfer of the human preproenkephalin gene to primary afferent nociceptors prevents phasic thermal allodynia/hyperalgesia in mice. It is not known, however, whether similar viral treatments would reverse ongoing or chronic pain and allodynia/hyperalgesia. To this end, mice were given intrathecal injections of pertussis toxin (PTX), which produces a weeks-long thermal hyperalgesia apparently by uncoupling certain G proteins from inhibitory neurotransmitter receptors. This treatment produced profound thermal hyperalgesia in both Adelta and C-fiber thermonociceptive tests lasting at least 6 weeks. However, treatment of skin surfaces with an enkephalin-encoding herpesvirus, but not control virus or vehicle, completely reversed this hyperalgesia. This profound anti-hyperalgesia was observed for both Adelta- and C-fiber-mediated responses. Interestingly, however, while the anti-hyperalgesic effect of the enkephalin-encoding virus on C-fiber-mediated responses was reversed by intrathecal application of micro or delta opioid antagonists, only delta antagonists reversed the effect of this virus on Adelta hyperalgesia. Thus, virus-mediated delivery of the proenkephalin cDNA reverses thermal hyperalgesia produced by PTX-induced ribosylation of inhibitory G proteins by an opioid-mediated mechanism. These results suggest that herpesvirus vectors encoding analgesic peptides may be useful in attenuating centrally mediated, ongoing neuropathic pain and/or hyperalgesia.

Administration, Cutaneous↗
PubMed2003

Serotonergic signaling inhibits hyperalgesia induced by spinal cord damage.

Although dysesthesia is one of the most serious problems in patients with spinal cord injury, most of them being unresponsive to conventional treatments. In this study, we established a rat thoracic spinal cord mild-compression model that revealed thermal hyperalgesia in the hind limb. The thoracic spinal cord was compressed gently, using a 20 g weight for 20 min. The withdrawal latency of the thermal stimulation of the bilateral hind-limb was monitored using Hargreaves' Plantar test apparatus. In this model, thermal-hyperalgesia was observed for 1 week after the injury. The spinal cord injury-induced thermal-hyperalgesia was mimicked by the intrathecal application of metergoline, a non-selective 5-HT antagonist, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl]-piperazine hydrobromide (NAN190), a selective 5-HT1 antagonist, and 3-tropanyl-3,5-dichlorobenzoate (MDL72222), a selective 5-HT3 antagonist. Intraperitoneal application of fluvoxamine maleate, a selective serotonin reuptake inhibitor, reduced the intensity of hyperalgesia induced by spinal cord injury. The inhibitory effect of fluvoxamine maleate on thermal hyperalgesia was prevented by the application of the aforementioned nonselective or selective 5-HT receptor antagonists. Intrathecal application of fluvoxamine maleate and selective 5-HT receptor agonists, i.e., 8-hydroxy-2-(di-n-proplyamino)-tetralin hydrobromide (8-OH-DPAT: 5HT-1 selective) and 2-methyl-5-hydroxytryptamine maleate (2-m-5-HT: 5HT-3 selective), inhibited the spinal cord injury-induced hyperalgesia. These results suggest that the change in the descending serotonergic signal plays an important role in hyperalgesia after the spinal cord injury, and that the application of selective serotonin reuptake inhibitors will be one of the candidates for new therapeutic methods against post-spinal cord injury dysesthesia.

Animals↗
PubMed1999

Effect of post-injury NMDA antagonist treatment on long-term Fos expression and hyperalgesia in a model of chronic neuropathic pain.

Chronic constriction injury (CCI) of the sciatic nerve results in persistent mechanical hyperalgesia together with Fos protein expression in the lumbar spinal cord. We have examined the relationship between mechanical hyperalgesia and Fos expression within the lumbar spinal cord on days 14, 35 and 55 after either CCI or sham operation. To determine the role of NMDA receptor mechanisms in the maintenance of hyperalgesia and Fos expression, the NMDA antagonist MK-801 (0.3 mg kg-1 s.c.) was administered daily on days 28 to 34 after operation. CCI animals developed unilateral hind limb hyperalgesia that persisted unchanged from days 14 to 55 of the study. MK-801 treatment reduced hyperalgesia by 57% (p=0.02) on day 35 in CCI animals but did influence hyperalgesia at day 55. In the spinal cord, Fos positive cells were present bilaterally throughout laminae 3-10 at all time points examined in both CCI and sham group animals. Fos counts ipsilateral to the side of injury in laminae 3-10 correlated significantly with hyperalgesia scores in the CCI but not sham animals. MK-801 treatment resulted in a suppression of Fos expression in ipsilateral laminae 3-4 (p=0.0017) and laminae 5-10 (p=0.0026) of CCI animals on day 35. Fos expression in sham group animals was not inhibited by MK-801 treatment at day 35. These results indicate that Fos expression is maintained by differing mechanisms following nerve injury or sham operation. The functional consequences of Fos expression following nerve injury and sham operation are discussed.

Animals↗
PubMed2001

p38 stress-activated protein kinase inhibitor reverses bradykinin B(1) receptor-mediated component of inflammatory hyperalgesia.

The effects of a p38 stress-activated protein kinase inhibitor, 4-(4-fluorophenyl)-2-(-4-methylsulfonylphenyl)-5-(4-pyridynyl) imidazole (SB203580), were evaluated in a rat model of inflammatory hyperalgesia. Oral, but not intrathecal, administration of SB203580 significantly reversed inflammatory mechanical hyperalgesia induced by injection of complete Freund's adjuvant into the hindpaw. SB203580 did not, however, affect the increased levels of interleukin-1beta and cyclo-oxygenase 2 protein observed in the hindpaw following complete Freund's adjuvant injection. Intraplantar injection of interleukin-1beta into the hindpaw elicited mechanical hyperalgesia in the ipsilateral paw, as well as in the contralateral paw, following intraplantar injection of the bradykinin B(1) receptor agonist des-Arg(9)-bradykinin. Oral administration of SB203580 1 h prior to interleukin-1beta administration prevented the development of hyperalgesia in the ipslateral paw and the contralateral bradykinin B(1) receptor-mediated hyperalgesia. In addition, following interleukin-1beta injection into the ipsilateral paw, co-administration of SB203580 with des-Arg(9)-bradykinin into the contralateral paw inhibited the bradykinin B(1) receptor-mediated hyperalgesia. In human embryonic kidney 293 cells expressing the human bradykinin B(1) receptor, its agonist des-Arg(10)-kallidin produced a rapid phosphorylation of endogenous p38 stress-activated protein kinase. Our data suggest that p38 stress-activated protein kinase is involved in the development of inflammatory hyperalgesia in the rat, and that its pro-inflammatory effects involve the induction of the bradykinin B(1) receptor as well as functioning as its downstream effector.

Animals↗
PubMed1999

Midazolam-induced hyperalgesia in rats: modulation via GABA(A) receptors at supraspinal level.

The effect of benzodiazepines on the nociceptive threshold was studied in rats using the tail-flick and the formalin tests. Systemic injection of midazolam (10 mg/kg, i.p.) induced a significant decrease of the tail-flick latency and produced a long-lasting nociceptive effect in the formalin test, thus characterising a hyperalgesic state. The hyperalgesia induced by midazolam in the tail-flick test was blocked by flumazenil, a specific antagonist for benzodiazepine sites associated with GABA(A) receptors. Picrotoxin, a Cl- channel blocker, inhibited midazolam-induced hyperalgesia in both tests. Midazolam caused hyperalgesia when administered intracerebroventricularly (i.c.v.; 25 microg) but not intrathecally (i.t.; 75 microg). I.c.v. but not i.t. (5 microg) injection of flumazenil suppressed the hyperalgesia induced by midazolam (10 mg/kg, i.p.). Combination of non-hyperalgesic doses of diazepam (10 mg/kg, i.p.) or ethanol (0.48 g/kg, oral) with midazolam (5 mg/kg, i.p.) also induced hyperalgesia. Our results demonstrate that midazolam and diazepam alone or in combination with ethanol can produce hyperalgesia by interacting with GABA(A) receptors at the supraspinal level in rats. The risk of hyperalgesia should be taken in account when these drugs are used in combination in humans.

Analysis of Variance↗
PubMed2002

Behavioral evidence supporting a differential role for spinal group I and II metabotropic glutamate receptors in inflammatory hyperalgesia in sheep.

A differential role for metabotropic glutamate receptors (mGluRs) in spinal nociception in normal animals has previously been identified. The present study examined the contribution of group I and group II mGluRs to the development and maintenance of inflammatory hyperalgesia produced by unilateral intradermal injection of carrageenan into the lower forelimb in sheep. Carrageenan (7.5 mg in 500 micro l) produced a significant bilateral reduction in forelimb mechanical withdrawal thresholds. Intrathecal administration of saline-vehicle or the group II mGluR antagonist (2S)-alpha-ethylglutamate (EGLU; 570 nmol) had no effect on either the development or maintenance of hyperalgesia. However, intrathecal administration of the group I mGluR antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; 450 nmol) before carrageenan blocked the development of ipsilateral hyperalgesia, and when given 2 h after carrageenan, reversed both ipsilateral and contralateral hyperalgesia. Intrathecal administration of the group II mGluR agonist (2S,1S,2S)-2-(carboxycyclopropyl)glycine (L-CCG-I; 620 nmol) given either before or after carrageenan treatment produced analgesia and anti-hyperalgesia, an effect abolished by co-administration of EGLU (570 nmol). The magnitude of the analgesic response, assessed by the area under the response curve, was significantly greater than that produced by LCCG-I in normal animals. These data demonstrate that the development and maintenance of inflammatory hyperalgesia is dependent on activation of group I mGluRs in spinal cord. In addition, the analgesic and anti-hyperalgesic actions of group II mGluRs suggest that these receptors play a crucial role in modulating acute inflammatory hyperalgesia.

Amino Acids, Dicarboxylic↗
PubMed1999

The role of systemic, spinal and supraspinal L-arginine-nitric oxide-cGMP pathway in thermal hyperalgesia caused by intrathecal injection of glutamate in mice.

The intrathecal (i.t.) administration of glutamate (10-100 nmol) caused dose-related hyperalgesia (mean ED50 of 35 nmol) when assessed in the thermal behaviour model of nociception, the hot-plate test maintained at 50 degrees C. The i.p., i.t. or intracerebroventricular (i.c.v.) injection of the nitric oxide synthase inhibitors, L-NOARG and L-NAME, did not induce any detectable effect per se, but instead, produced dose-related inhibition of glutamate-induced hyperalgesia. D-NAME, the inactive enantiomer of L-NAME, had no effect. The i.c.v. or i.t. administration of L-NIO caused graded attenuation of glutamate-induced hyperalgesia. L-arginine (3.4 mmol kg(-1), i.p.), but not D-arginine (3.4 mmol kg(-1), i.p.) significantly potentiated glutamate (10 nmol)-induced hyperalgesia, an action that was prevented by L-NOARG (137 nmol kg(-1)). The co-injection of S-nitroso-N-acetyl-D,L-penicillamine (SNAP) (0.22 micromol) or 8-bromo-cGMP (22.5 nmol) with glutamate (10 nmol), via either i.t. or i.c.v. routes, also significantly enhanced glutamate-induced hyperalgesia. The guanylate cyclase inhibitors LY 83583 (0.1-1.0 nmol) or ODQ (30-300 pmol) co-administered with glutamate, dose-dependently antagonised the glutamate-induced hyperalgesia. Collectively, these results demonstrate that the i.t. injection of glutamate into the spinal cord of mice produces dose-related hyperalgesia an effect that was largely mediated by the L-arginine-nitric oxide-cGMP pathway from both spinal and supraspinal sites.

Analysis of Variance↗
PubMed2003

Onset and recovery of hyperalgesia and hyperexcitability of sensory neurons following intervertebral foramen volume reduction and restoration.

OBJECTIVE: To investigate the relationships between L4 and L5 intervertebral foramen (IVF) stenosis (IVFS), as well as the restoration and onset and recovery of behavioral hyperalgesia and alterations in primary sensory neuron excitability. METHODS: IVFS was produced by surgically implanting stainless steel rods unilaterally into the intervertebral foramen at L4 and L5. The insertion of a stainless steel rod in the IVF caused IVF volume reduction, which mimics IVFS. The rods were kept for up to 14 weeks in 16 rats and 2 to 4 weeks in another 32 rats. Rod withdrawal was expected to restore the IVF volume. The rods were withdrawn in 20 rats on the 7th day and in another 20 rats on the 14th day, postoperatively. Two additional groups of control rats received no surgery or sham operation. Behavioral hyperalgesia was evidenced by the significantly decreased threshold and shortened latency of foot withdrawal to mechanical and thermal stimulation of the plantar surface. Electrophysiological intracellular recordings were obtained in vitro from L4 and/or L5 dorsal root ganglia (DRG). RESULTS: The IVFS rats exhibited a rapid-onset (</=1 day), long-lasting (10-11 weeks), mechanical, and thermal hyperalgesia. DRG neurons in each category, large-sized, medium-sized, and small-sized, from IVFS rats were more excitable than those from control rats, evaluated by the significantly decreased threshold current and action potential threshold and increased number of discharges evoked by depolarizing current and incidence of spontaneous activity. IVF volume restoration significantly reduced behavioral hyperalgesia and the increased excitability of DRG neurons. In contrast, sham surgery produced no behavioral or electrophysiological changes in the ganglion neurons. CONCLUSION: The present study demonstrates that hyperalgesia and hyperexcitability of the primary sensory neurons can be induced following the IVF volume reduction produced by insertion of a stainless steel rod and mostly relieved by the rod withdrawal. The recovery of excitability of DRG cells to normal levels is associated with the abatement of hyperalgesia. These results support the hypothesis that increased excitability of DRG neurons is associated with the generation and maintenance of hyperalgesia and suggest that relief of the IVF stenosis, which could compress all of the normal constituents within the IVF (ie, DRG, nerve root, blood and lymph vessels, adipose, etc.), may help to alleviate chronic pain in humans.

Analysis of Variance↗
PubMed2003

A comparison of hyperalgesia and neurogenic inflammation induced by melittin and capsaicin in humans.

Melittin (a main compound of bee venom) and capsaicin were injected intradermally in healthy human volunteers: (1) to study secondary mechanical hyperalgesia (static hyperalgesia and dynamic hyperalgesia) around the injection site; and (2) to correlate the sensory changes to the neurogenic inflammation assessed by laser-doppler blood flowmetry. Melittin 50 microg and capsaicin 10 microg induced comparable spontaneous pain and increased blood flow (neurogenic inflammation). Intradermal injection of melittin induced regions of secondary mechanical hyperalgesia around the injection site, however, they were not as large as the hyperalgesia induced by capsaicin. This is the first report studying mechanical hyperalgesia induced by melittin in humans, and the results were in agreement with the previous observations in rats. Melittin seems to be a valuable model to study a possible contribution of neurogenic inflammation to hyperalgesia in humans.

Analysis of Variance↗
PubMed2000

Mechanical hyperalgesia after an L5 spinal nerve lesion in the rat is not dependent on input from injured nerve fibers.

An injury to a peripheral nerve in animals often leads to signs of neuropathic pain including hyperalgesia to heat, cold and mechanical stimuli. The role of injured and intact nerve fibers in mechanical hyperalgesia was evaluated in rats subjected to an L5 spinal nerve ligation-and-cut ('modified SNL lesion'). To assess the contribution of injured afferents, an L5 dorsal rhizotomy was performed immediately before, or 7 days after the modified SNL lesion. To study the role of adjacent intact spinal nerves, an L4 dorsal rhizotomy was performed 7 days after the modified SNL lesion. The up-down method of Dixon (Dixon WJ, Annu Rev Pharmacol Toxicol 1980;20:441-462) was used to measure the paw withdrawal threshold to mechanical stimuli at three sites on the rat hindpaw corresponding to the L3, L4, and L5 dermatomes. We found that the modified SNL lesion produced a significant, lasting (20 days) decrease of the mechanical withdrawal threshold. The severity and duration of mechanical hyperalgesia varied across testing sites. The L5 and L4 dermatome test sites developed the most severe and lasting mechanical hyperalgesia. In contrast, the L3 testing site developed significantly less severe and shorter lasting mechanical hyperalgesia. L5 dorsal rhizotomy, by itself, produced a transient decrease in mechanical withdrawal thresholds. L5 dorsal rhizotomy performed before, or 7 days after, the modified SNL lesion did not prevent or resolve the observed decrease in mechanical withdrawal thresholds. L4 dorsal rhizotomy performed 7 days after the modified SNL lesion resulted in an immediate reversal of mechanical withdrawal thresholds back to baseline values. These results suggest that, after L5 spinal nerve ligation-and-cut, mechanical hyperalgesia develops and persists independent of input from injured afferents. We propose that the Wallerian degeneration that develops after a nerve injury leads to interactions between the degenerating fibers of the injured spinal nerve and the intact fibers of adjacent spinal nerves. This leads to changes in the intact fibers that play a critical role for both initiation and maintenance of mechanical hyperalgesia.

Animals↗
PubMed2000

Effect of pre- or post-traumatically applied i.v. lidocaine on primary and secondary hyperalgesia after experimental heat trauma in humans.

Hyperalgesia on intradermal capsaicin application can be attenuated by systemic application of local anesthetics. We tested whether low doses of local anesthetics applied pre- or post-traumatically can reduce heat trauma-induced primary and secondary hyperalgesia in humans. Six healthy volunteers consented to the randomized, double-blind, and cross-over designed study. In each subject, a first-degree burn injury was induced three times (corresponding to a pre-traumatic, post-traumatic and control group) at an interval of at least 3 weeks. Heat was applied by a computer-controlled Peltier thermode (47 degrees C, 5 min). In the pre-traumatic group, lidocaine infusion was commenced 30 min prior to heat trauma, and in the post-traumatic group immediately after heat trauma for a total infusion time of 60 min each. Volunteers rated pain on a visual analogue scale (VAS) between threshold and tolerance maximum (0-100% VAS). Primary hyperalgesia was quantified by determining mechanical (von Frey hairs) and thermal (Peltier thermode) pain thresholds. Secondary hyperalgesia was quantified by determining the area in which normally unpleasant von Frey hairs evoked pain or tenderness. Baseline thermal and mechanical pain thresholds did not differ between groups. Heat application always resulted in a first-degree burn injury including both primary and secondary hyperalgesia. The former remained by and large stable for about 4 h whereas the latter continuously increased within the first 2 h. Lidocaine did not affect primary hyperalgesia, irrespective of pre- or post-traumatic application, but substantially reduced the development of secondary hyperalgesia on pre-traumatic, and for tendency on post-traumatic infusion (treatment groups did not differ significantly). Burn injury-induced erythema was smallest in the pre-traumatic group and largest in the control group; however, the level of significance was not reached. Plasma concentrations of lidocaine were always higher than 1.5 microg/ml 30 min after bolus application of lidocaine and reached a peak of 2-3 microg/ml after about 1 h. Thus, local anesthetics at concentrations that do not block nerve conduction substantially affect ongoing central changes in pain processing that are induced by a real tissue trauma. A significant preemptive effect could not be demonstrated. The anti-hyperalgesic effect of lidocaine is likely based on action of central (spinal) sites, but peripheral sites may also be addressed.

Adult↗
PubMed2002

Enhanced reduction in hyperalgesia by combined administration of clonidine and TENS.

Transcutaneous electrical nerve stimulation (TENS) partially reduces primary hyperalgesia and is frequency dependent such that high frequency TENS produces approximately a 30% reduction in hyperalgesia whereas low frequency TENS has no effect. Both high and low frequency TENS completely reduce secondary hyperalgesia by activation of mu and delta- opioid receptors in the spinal cord and rostral-ventral medulla suggesting an opiate mediated analgesia. Clonidine in combination with opiates produces a synergistic interaction such that there is a potentiated reduction in hyperalgesia. Thus, we tested if combined application of clonidine with TENS would enhance the reduction in primary hyperalgesia. Male Sprague-Dawley rats were inflamed by subcutaneous injection of 3% carrageenan into one hindpaw. Withdrawal latency to radiant heat and withdrawal threshold to mechanical stimuli were assessed before and after inflammation and after administration of clonidine (0.002-2 mg/kg, intraperitoneal (i.p.)) with either low (4 Hz) or high (100 Hz) frequency TENS. Clonidine alone reduced both heat and mechanical hyperalgesia with ED50s of 0.02 and 1.0 mg/kg, respectively. In combination with either low or high frequency TENS, the dose-response curve shifted to the left and was significantly different from clonidine alone. The ED50s for heat and mechanical hyperalgesia following low frequency TENS with clonidine were 0.002 and 0.2 mg/kg, respectively and those following high frequency TENS with clonidine were 0.005 and 0.15 mg/kg, respectively. Thus, combined use of clonidine and TENS enhances the reduction in analgesia produced by TENS and enhances the potency of clonidine. It would thus be expected that one would reduce the side effects of clonidine and enhance analgesic efficacy with combinations of pharmaceutical and non-pharmaceutical treatments.

Analgesics↗