Unilateral hindpaw inflammation induces bilateral activation of the locus coeruleus and the nucleus subcoeruleus in the rat

Several lines of evidence have shown that unilateral hindpaw inflammation produces activation of the locus coeruleus (LC) and the nucleus subcoeruleus (SC), resulting in descending modulation of nociceptive processing in the dorsal horn. However, it is unclear if the LC/SC is activated unilaterally or bilaterally following the development of unilateral hindpaw inflammation. The present study was designed to clarify this question. For the induction of unilateral hindpaw inflammation, lambda carrageenan (2.0mg in 0.15ml saline) was injected subcutaneously into the plantar surface of the left hindpaw. Four hours after carrageenan injection, in the LC/SC both ipsilateral and contralateral to the inflamed paw, the number of Fos-positive cells increased significantly in carrageenan-injected rats when compared to vehicle (saline)-injected and untreated control rats. The Fos expression in the LC/SC was equivalent bilaterally in the carrageenan-injected rats, as well as in vehicle-injected and untreated control rats. For nociceptive testing, the paw withdrawal latency, which measures cutaneous hyperalgesia in response to thermal stimuli, was determined in rats receiving a unilateral lesion of the LC/SC either ipsilateral or contralateral to the inflamed paw. Two and a half hours after the induction of inflammation, in both groups of rats with unilateral lesion, paw withdrawal latencies decreased significantly in the LC/SC-lesioned rats. However, there was no significant difference in paw withdrawal latencies between the LC/SC-lesioned rats and sham-operated rats, indicating that unilateral activation of the LC/SC is sufficient for modulating nociceptive processing in the dorsal horn. These results suggest that unilateral hindpaw inflammation induces bilateral activation of the LC/SC.     

Neurochemical evidence for inflammation-induced activation of the coeruleospinal modulation system in the rat

By using the microdialysis technique, the concentration of noradrenaline (NA) in the dorsal horn during unilateral hindpaw inflammation was compared between rats receiving bilateral lesions of the locus coeruleus (LC) and non-operated control rats. Bilateral lesions of the LC were made using an anodal current one week before testing. Unilateral hindpaw inflammation was produced by a subcutaneous injection of carrageenan (6 mg in 0.15 ml saline). Under conditions of sodium pentobarbital anesthesia, the microdialysis probe was inserted into the dorsal horn either ipsilateral or contralateral to the site of inflammation. The NA concentration in the dialysate was measured by high-performance liquid chromatography with electrochemical detection. Prior to carrageenan injection, the NA level (baseline level) did not differ between the LC-lesioned and the non-operated groups. After carrageenan injection, in the non-operated rats, the NA level increased significantly compared to the baseline level only in the dorsal horn ipsilateral to the site of inflammation, but not in the dorsal horn contralateral to the site of inflammation. An increase of the NA level was not observed in the LC-lesioned rats and in rats receiving an injection of saline. The result suggests that unilateral hindpaw inflammation produces excitation of descending NA-containing neurons from the LC, resulting in an increase of the NA level in the dorsal horn ipsilateral to the site of inflammation.     

Effects of lesions of locus coeruleus/subcoeruleus on diffuse noxious inhibitory controls in the rat.

Diffuse noxious inhibitory controls (DNIC) acting on trigeminal convergent neurons were compared in sham-operated animals and rats with quinolinic acid induced lesions of the locus coeruleus/subcoeruleus (LC/SC). No significant differences were observed between control animals and those with ipsilateral, contralateral or bilateral lesions of the LC/SC, in respect of: (1) the general properties of the recorded units; and (2) the magnitude of the depressions of C-fiber-evoked responses of convergent neurons produced by immersing each paw in a 50 degrees C water bath (i.e. DNIC). It is concluded that the LC/SC is not involved, at least directly, in the supraspinal part of the loop which subserves DNIC in the rat.     

Disruption of glial function enhances electroacupuncture analgesia in arthritic rats

Activated glia play a major role in mediating behavioral hypersensitive state following peripheral inflammation. Electroacupuncture is well known to relieve persistent inflammatory pain. The present study was undertaken to examine whether fluorocitrate, a glial metabolic inhibitor, could synergize electroacupuncture antagonizing thermal hyperalgesia and mechanical allodynia evoked by ankle joint inflammation. Monoarthritis of rat ankle joint was induced by an intra-articular injection of Complete Freund's Adjuvant (CFA). The paw withdrawal latency (PWL) from a thermal stimulus and paw withdrawal threshold (PWT) from von Frey hairs were measured in awake rats. Intrathecal (i.t.) injection of 1 nmol fluorocitrate markedly suppressed monoarthritis-induced thermal hyperalgesia and mechanical allodynia. Unilateral electroacupuncture stimulation of "Huantiao" (GB30) and "Yanglingquan" (GB34) acupuncture points (100/2 Hz alternation, 1-2-3 mA) significantly elevated the PWLs and PWTs for 45 min after cessation of electroacupuncture in monoarthritic rats. Co-application of 0.1 or 1 nmol fluorocitrate with electroacupuncture significantly potentiated electroacupuncture analgesia, although 0.1 nmol fluorocitrate alone had no effect on PWLs and PWTs in monoarthritic rats. These results suggested that electroacupuncture and disrupting glial function could synergistically antagonize inflammatory pain, which might provide a potential strategy for the treatment of arthritic pain.     

Unilateral nerve injury produces bilateral loss of distal innervation

There are no known anatomical connections between neurons that innervate homologous right and left body parts. Nevertheless, some patients develop bilateral abnormalities after unilateral injury, a phenomenon often unrecognized and not yet characterized. Therefore, we examined in rats the effects of ligating and cutting one tibial nerve on sensory function and on density of innervation in hind paws contralaterally as well as ipsilaterally to the injury, at times between 1 day and 5 months after surgery. Punches removed from tibial- or sural-innervated planter paw skin were immunolabeled to quantitate epidermal nerve endings. Naive and sham-operated rats provided controls. Axotomized rats had near-total loss of PGP9.5(+) innervation within ipsilateral tibial-innervated skin at all time-points. Adjacent ipsilateral sural-innervated skin had persistent hyperalgesia without denervation, and robust axonal sprouting at 5 months after surgery. Contralesional hind paws lost 54% of innervation in tibial-innervated epidermis starting 1 week after surgery and persisting throughout. Contralesional sural-innervated skin had neither neurite loss nor sprouting. These results imply that unilateral nerve injury can cause profound, long lasting, nerve-branch-specific loss of distal innervation contralaterally as well as ipsilaterally. They discredit the practice of using tissues contralateral to an injury to provide normative controls and suggest the possibility of rapid, transmedian postinjury signals between homologous mirror-image neurons.     

Altered c-fos expression in the parabrachial nucleus in a rodent model of CFA-induced peripheral inflammation

Increases in the expression of immediate early genes have been shown to occur in the lumbar spinal cord dorsal horn after peripheral inflammation. Given that the pontine parabrachial nucleus has been implicated in nociceptive as well as antinociceptive processes and is reciprocally connected with the spinal cord dorsal horn, it seems likely that peripheral inflammation will cause alterations in immediate early gene expression in this nucleus. To test this hypothesis we examined cFos-like immunoreactivity in a rodent complete Freund's adjuvant-induced peripheral inflammatory model of persistent nociception. Unilateral hind paw injections of complete Freund's adjuvant produced inflammation, hyperalgesia of the affected limb, and alterations in open field behaviors. Immunocytochemical analysis demonstrated a bilateral increase in cFos-like immunoreactivity in the lateral and Kolliker-Fuse subdivisions of the parabrachial nucleus at 6 and 24 hours postinjection and an ipsilateral decrease below basal levels in the Kolliker-Fuse subdivision at 96 hours postinjection when compared to saline controls. Taken together, these results suggest that select parabrachial neurons are activated by noxious somatic inflammation. These active parabrachial neurons are likely to participate in ascending nociceptive and/or descending antinociceptive pathways. © 1996 Wiley-Liss, Inc.     

Sex-related differences in descending norepinephrine and serotonin controls of spinal withdrawal reflex during intramuscular saline induced muscle nociception in rats

Sex-associated differences in the perception and modulation of pain have widely been reported in humans as well as animals. The aim of the present study performed in conscious rats of both sexes was to systematically investigate the role of sex in endogenous descending controls of nociceptive paw withdrawal reflex during experimental muscle pain elicited by intramuscular (i.m.) injection with different doses (0.1–0.4 ml of 0.9–5.8%) of saline. Ipsilateral i.m. injection of 0.2–0.4 ml, but not 0.1 ml, isotonic (0.9%, IT) saline elicited long lasting (about 7 d), secondary and contralateral mechanical hyperalgesia in female rats, whereas male rats exhibited a bilateral, short-term (less than 1 d) mechanical hyperalgesia only during the exposure to 0.4 ml IT saline injection (P < 0.05). A bolus of 0.4 ml, but not 0.1–0.2 ml, IT saline significantly induced a one-week, secondary and contralateral heat hypoalgesia in both male and female rats (P < 0.05). In contrast to the IT saline injection, 0.1 ml hypertonic (5.8%, HT) saline started to evoke bilateral mechanical hyperalgesia in male and female rats. During the HT saline induced muscle nociception, mechanical hyperalgesia in female rats was greater in magnitude and longer in duration than that of in male rats (P < 0.05). Heat hypoalgesia was bilaterally found in male rats receiving either 0.2 ml or 0.4 ml HT saline injection, whereas female rats showed heat hypoalgesia, subjected only to the 0.4 ml HT saline injection (P < 0.05 and P < 0.001). Intrathecal (i.th.) administration of either 6-hydroxydopamine hydrobromide (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT) significantly attenuated the HT saline induced heat hypoalgesia, not mechanical hyperalgesia, in male rats. By contrast, in female rats i.th. 6-OHDA markedly blocked heat hypoalgesia, and mechanical hyperalgesia was prevented by 5,7-DHT treatment. It is suggested that i.m. injection of saline dose-dependently elicits ipsilateral secondary and contralateral mechanical hyperalgesia and heat hypoalgesia, which are differently modulated by descending noradrenaline (NA) and serotonin (5-HT) pathways in rats of both sexes. Importantly, the present findings here are not only consistent with our previous study indicating a supraspinal nociception discriminator with different triggering thresholds to govern peripheral A-δ and C-fiber mediated responses (You et al., 2010), but further strengthen this hypothesis that compared with male rats, supraspinal nociception discriminator in female rats exhibits a lower facilitatory threshold and a higher inhibitory threshold. This may bring our attention to better understand why females are commonly reported to be more sensitive and less tolerant to noxious stimulation.In conclusion, sex-related differences are important in descending modulations of pain and anesthesia. Less noxious stimuli could activate descending inhibition in males but not females, whereas less noxious afferents may elicit descending facilitation in female, but not male rats. Central noradrenergic and serotonergic pathways are differently involved in the action of descending modulations of nociception in rats of both sexes.     

Post-injury treatment with GM1 ganglioside reduces nociceptive behaviors and spinal cord metabolic activity in rats with experimental peripheral mononeuropathy

In a rat model of painful peripheral mononeuropathy, this study examined the effects of post-injury treatment with a monosialoganglioside, GM1, on abnormal nociceptive behaviors and spinal cord neural activity resulting from loose ligation of the rat common sciatic nerve (chronic constrictive injury, CCI). Thermal hyperalgesia and spontaneous pain behaviors of CCI rats were assessed by measuring foot-withdrawal latencies to radiant heat and by rating spontaneous hind paw guarding positions, respectively. Neural activity within different regions of the spinal cord was inferred in both CCI and sham-operated rats by employing the [14C]-2-deoxyglucose (2-DG) autoradiographic technique to measure spinal cord glucose metabolism. Intraperitoneal (i.p.) GM1 treatment (10 mg/kg) initiated 1 h or 24 h after injury and once daily for the first 9 post-injury days reduced thermal hyperalgesia of the hind paw ipsilateral to nerve ligation and lowered spontaneous pain behavior rating scores in CCI rats. Sciatic nerve ligation reliably increased basal 2-DG metabolic activity of CCI rats in all four sampled regions (laminae I-IV, V-VI, VII, VIII-IX) of spinal cord lumbar segments (L2-L5) both ipsilateral and contralateral to nerve ligation 10 days after injury. Consistent with the drug's effects on spontaneous pain behaviors, 10 daily GM1 treatments (10 mg/kg, i.p.) initiated 1 h after nerve ligation reduced spinal cord 2-DG metabolic activity in laminae V-VI and VII ipsilateral to nerve ligation and in all four sampled regions contralateral to nerve ligation. This attenuation of the increased spinal cord glucose utilization that occurs in the absence of overt peripheral stimulation may reflect an influence of GM1 on increased neural activity contributing to spontaneous pain. Since gangliosides are thought to protect neurons from excitotoxic effects of excitatory amino acids, these results suggest that ganglioside treatment may result in attenuation of excitatory neurotoxicity that may occur following peripheral nerve injury. Thus, ganglioside treatment could provide a new approach to the clinical management of neuropathic pain syndromes following peripheral nerve injury.     

Cutaneous hyperalgesia: contributions of the peripheral and central nervous systems to the increase in pain sensitivity after injury

This study assesses the contributions of the peripheral and central nervous systems in the development of hyperalgesia (increased pain sensitivity) after an injury. Experiments were carried out to examine the role of C-fiber afferents, the spinal cord and sympathetic efferents on inflammation, primary hyperalgesia and referred hyperalgesia produced in rats by a heat injury. A peripheral mechanism was indicated since both primary hyperalgesia and inflammation after a heat injury were significantly attenuated by blocking C-fiber afferents with local capsaicin. In addition, a central mechanism was indicated since the spread of hyperalgesia to the paw contralateral to a heat injury was prevented by either spinal anesthesia or the blocking of sympathetic efferents by guanethidine. A further role for central mechanisms was indicated since referred hyperalgesia--the enhancement of self-mutilation (autotomy) of a denervated limb which had previously sustained a heat injury--was reduced by spinal anesthesia or a combined blocking of C-fiber afferents and sympathetic efferents with intrathecal capsaicin + guanethidine. The results strongly suggest that referred hyperalgesia after a heat injury is dependent on increased spinal cord activity. However, autotomy in rats that did not undergo a previous injury was unaffected by either spinal anesthesia or intrathecal capsaicin. This suggests that spinal cord hyperactivity, although it plays a role in hyperalgesia following a heat injury, is not a crucial factor in producing pain and hyperalgesia after a nerve injury.     

Periaqueductal gray stimulation produces a spinally mediated, opioid antinociception for the inflamed hindpaw of the rat

The objective of the present study was to characterize stimulation-produced antinociception from the periaqueductal gray matter (PAG) in rats with unilateral hindlimb inflammation induced by an intraplantar injection of Freund's complete adjuvant. Rats were chronically implanted with a bipolar stimulating electrode in the PAG. Nociception was assessed using a paw pressure test. Prior to inflammation, PAG stimulation significantly increased paw pressure threshold in both paws compared to non-stimulated controls. Following inflammation, PAG stimulation inhibited nociception in the inflamed, but not the non-inflamed paw. Systemic administration of naloxone blocked antinociception from ventral, but not dorsal PAG stimulation sites. Intrathecal, but not subcutaneous, administration of quaternary naltrexone completely blocked stimulation-produced antinociception from the PAG. The known increased levels of endogenous opioids occurring in the spinal cord ipsilateral to the site of inflammation suggest a mechanism for the selective antinociceptive effect of ventral PAG stimulation seen for the inflamed paw.     

Antihyperalgesia effect of BmK AS,a scorpion toxin,in rat by intraplantar injection

The antihyperalgesia effect of BmK AS, a novel sodium channel-specific polypeptide modulator from Chinese scorpion venom in rats was investigated in this study. PWLs (paw withdrawal latency) were increased to 150+/-28, 203+/-34 and 250+/-17% of the control by administration of BmK AS (10 microl) at the concentration of 0.001, 0.01 and 0.1 mg/ml in carrageenan-induced inflamed rats, respectively. Meanwhile, PWLs were enhanced to about 126+/-4, 132+/-4 and 140+/-6% of the control at the same applied concentration of BmK AS in normal rats. The results suggest that BmK AS can induce peripheral antihyperalgesia and antinociception, which probably by modulating the sodium channel on nociceptive afferent pathway.     

Roles of monoaminergic, glycinergic and GABAergic inhibitory systems in the spinal cord in rats with peripheral mononeuropathy

The current study was designed to determine if the monoaminergic descending inhibitory system and the glycinergic and GABAergic inhibitory systems were activated in the spinal cord in the presence of peripheral mononeuropathy produced by loose ligatures around the common sciatic nerve. The time course of withdrawal latencies to thermal stimuli were assayed in lesioned and sham-operated rats. The levels of monoamines (serotonin; 5-HT, noradrenaline, and dopamine), glycine and γ-aminobutyric acid (GABA) in the dorsal half of the spinal cord were measured using HPLC with electrochemical detection. Furthermore, on day 7 after nerve ligation, intrathecal methysergide, yohimbine, strychnine or bicuculline was administered in order to investigate the roles of these inhibitory neuromodulators in this pathological pain state. The levels of 5-HT and noradrenaline significantly increased in both ipsi- and contralateral sides of the dorsal half of the lumbar spinal cord in the lesioned, but not sham-operated animals. The levels of glycine and GABA in the ipsilateral dorsal half of the spinal cord increased significantly and were significantly higher than in the contralateral side. Intrathecal antagonists of 5-HT, noradrenaline, glycine and GABA produced enhancement of the magnitude of hyperalgesia on the lesioned hindpaw. We also examined the effects of four daily single treatments with intrathecal MK-801 beginning 15 min prior to nerve ligation on the development of thermal hyperalgesia and on the contents of the neuromodulators in the ligation model. MK-801 treatment effectively abolished the increases in 5-HT, noradrenahne, glycine and GABA levels as well as preventing the development of hyperalgesia. The results of the present study suggest that the pathological pain state activates or increases the activity of these inhibitory systems.     

Involvement of spinal neurokinin-1 receptors in the maintenance but not induction of carrageenan-induced thermal hyperalgesia in the rat

The study was undertaken to assess the antihyperalgesic effect of L-732,138, (N-acetyl-L-tryptophan-3,5-bistrifluoromethyl benzyl ester), a non-peptide neurokinin-1 (NK1) receptor antagonist in rats when given intrathecally. The peripheral inflammation associated with behavioral hyperalgesia to a thermal stimulus was induced by intraplantar (i.pl.) injection of carrageenan. The thermal hyperalgesia was measured by paw withdrawal latency. Intrathecal (i.t.) injection of L-732,138 (100 nmol) at 3h after carrageenan markedly attenuated the paw withdrawal latency of the inflamed paw, but not that of the non-inflamed paw. L-732,138 (100 nmol, i.t.) given 10 min prior to carrageenan injection had no effect on the carrageenan-induced decrease in paw withdrawal latency to noxious thermal stimulus. The results demonstrate that NK1 receptor is involved in the maintenance but not the induction and development of thermal hyperalgesia evoked by carrageenan.     

Influence of spinalization on spinal withdrawal reflex responses varies depending on the submodality of the test stimulus and the experimental pathophysiological condition in the rat

The influence of midthoracic spinalization on thermally and mechanically induced spinal withdrawal reflex responses was studied in the rat. There were three experimental groups of rats: healthy controls, rats with a spinal nerve ligation-induced unilateral neuropathy, and rats with a carrageenan-induced inflammation of one hindpaw. Tail flick response was induced by radiant heat. Hindlimb withdrawal was induced by radiant heat, ice water, and innocuous or noxious mechanical stimulation of the paw. Prior to spinalization, spinal nerve ligated and carrageenan-treated animals had a marked unilateral allodynia and hyperalgesia. Spinalization tended to induce a facilitation of noxious heat-evoked reflexes. This spinalization-induced facilitation was stronger on tail than hindlimb withdrawal. Spinalization-induced skin temperature change did not explain the facilitation of noxious heat-evoked reflexes. In contrast, spinal withdrawal responses induced by noxious cold or mechanical stimulation were significantly suppressed following spinalization. The spinalization-induced facilitatory effects as well as inhibitory ones on spinal reflexes were enhanced in inflamed/neuropathic animals. The results indicate that the tonic descending control of spinal nocifensive responses varies depending on the submodality of the test stimulus, the segmental level of the reflex (tail vs. hindlimb), and on the pathophysiological condition.     

The role of norepinephrine in adult rat somatosensory (SmI) cortical metabolism and plasticity

Stimulation of rat facial vibrissae increases glucose utilization in the corresponding barrels (lamina IV) and associated columns in laminae I-VIa of the contralateral first somatosensory (SmI) cortex as assessed autoradiographically by the uptake of [14C]2-deoxy-glucose (2-DG). Chronic deafferentation (2 months) by bilateral vibrissectomy with sparing of the C3 vibrissa (SC3) in adult Sprague-Dawley rats produced no change in the rate of LCGU but led to an increased areal extent of the metabolic representation of the SC3 barrel (39%, P less than 0.001) and column (31%, P less than 0.003) as compared to rats with fully intact vibrissae. In other rats with intact facial vibrissae, 6-hydroxydopamine lesions of the locus coeruleus (LC) depleted ipsilateral cortical norepinephrine (NE) by more than 90% and, 2 months later, led to an 11% and 21% increase in C3 barrel and column metabolic representations, respectively, as compared to the contralateral SmI cortex with intact NE levels (P less than 0.05). When bilateral vibrissectomy was combined with a unilateral LC lesion, the SC3 barrel and column metabolic representation on the LC-intact side enlarged as expected but no enlargement occurred on the NE-depleted side (20% difference; P less than 0.05). Therefore, the effect of NE on the SmI cortex depends on the status of its afferent input. NE inhibits the spread of metabolic activity beyond the activated barrel and column in the intact cortex, but independently modulates plastic enlargement in the partially deafferented SmI cortex.     

Altered Calcitonin Gene-related Peptide, Substance P and Enkephalin Immunoreactivities and Receptor Binding Sites in the Dorsal Spinal Cord of the Polyarthritic Rat

The dorsal horn of the spinal cord, which forms the locus of first synapses in pain pathways, is an important site of interaction between calcitonin gene-related peptide (CGRP), substance P and enkephalin—the neuropeptides considered to be especially involved in the regulation of pain perception. Since adjuvant-induced arthritic rats provide a suitable model for peripheral inflammation and hyperalgesia, the possible alterations of immunoreactive CGRP, substance P and enkephalin as well as the binding sites for [¹²⁵I]hCGRPα, [¹²⁵I]substance Plneurokinin-1, (NK1) and [¹²⁵I]FK-33-824/μ-opioid receptors were studied in the dorsal horn of the spinal cord receiving projections from the inflamed limbs. In arthritic rats compared to control animals, a bilateral increase in CGRP- and substance P-immunoreactive fibres and the presence of enkephalin-immunoreactive cell bodies were noted in the dorsal horn of the spinal cord. As for receptors, while a significant decrease in [¹²⁵I]hCGRPα and [¹²⁵I]substance P/NK1 binding sites was observed in selective layers, no measurable alteration in [¹²⁵I]FK-33-824/μ-opioid binding sites was noted in any regions of the arthritic rat dorsal horn compared to the unaffected control rats. Following unilateral section of the peripheral nerve prior to induction of arthritis, CGRP- and substance P-immunoreactive fibres were markedly depleted and no enkephalin-positive neurons were observed in the ipsilateral dorsal horn. Analysis of receptor binding sites in denervated arthritic rats, however, exhibited differential responses, i.e. a significant increase in [¹²⁵I]hCGRPα, a marked decrease in [¹²⁵I]FK-33-824/μ-opioid and apparently no alteration in [¹²⁵I]substance P/NK1 receptor binding sites were observed in the ipsilateral dorsal horn compared to the intact contralateral side. These results taken together provide anatomical evidence for a concerted role of these peptides in the regulation of adjuvant-induced hyperalgesia accompanying peripheral inflammation.     

Kynurenic acid enhances electroacupuncture analgesia in normal and carrageenan-injected rats

The interaction between electroacupuncture (EA) and an intrathecally administered wide-spectrum excitatory amino acid (EAA) receptor(s) antagonist, kynurenic acid (KYNA) on carrageenan-induced thermal hyperalgesia and spinal Fos expression was investigated. Intrathecal (i.t.) injection of 0.1, 1, 10, and 100 nmol KYNA markedly and dose-dependently increased the latency of paw withdrawal (PWL) of the carrageenan-injected paw. While the PWLs of the non-injected and normal saline (NS)-injected paws were not obviously affected by application of KYNA at the doses tested. Intrathecal injection of 0.1 nmol KYNA significantly potentiated the anti-nociception induced by EA stimulation of contralateral 'Zu-San-Li' and 'Kun-Lun' acupoints either in the carrageenan- or NS-injected rats. Three hours after intraplantar (i.pl.) injection of carrageenan, the number of Fos-like immunoreactive (Fos-LI) neurons was significantly increased in all layers of ipsilateral spinal cord at L(4)-L(5) with the higher density in laminae I-II and V-VI. Intrathecally pre-administered KYNA (10 nmol) significantly reduced the total number of carrageenan-induced Fos-LI neurons with more apparent reduction in laminae I-II and IV-V. Pre-coapplication of 10 nmol KYNA and EA of bilateral 'Zu-San-Li' and 'Kun-Lun' acupoints, the numbers of carrageenan-induced Fos-LI neurons in laminae I-II and V-VI further reduced. The level of Fos expression in the spinal cord induced by carrageenan was significantly lower compared with that of i.t. injection of KYNA or EA alone. These results demonstrated that EAA receptor(s) antagonist could enhance EA-induced anti-nociception and anti-hyperalgesia.     

Differential effects of unilateral striatal and nigrostriatal lesions on grip strength, skilled paw reaching and drug-induced rotation in the rat

Lateralised motor deficits associated with basal ganglia dysfunction were compared in separate groups of rats receiving unilateral 6-hydroxydopamine-induced lesions of the dopaminergic nigrostriatal pathway, quinolinic acid-induced lesions of the striatum, or sham control injections. Amphetamine induced ipsilateral rotation in both lesion groups, whereas a low ('supersensitive') dose of apomorphine induced rotation only in the nigrostriatal lesion group. Both lesions induced impairments in skilled paw reaching with the contralateral paw in the 'staircase' test; by contrast the striatal lesions also induced a marked impairment with the ipsilateral paw, which was unaffected by the nigrostriatal lesion. A previously reported increase in grip strength with the contralateral paw after nigrostriatal lesion was replicated, whereas striatal lesions induced only minor bilateral deficits in this test. The results are discussed in the context of the utility, reliability and validity of alternative tests of motor deficit in animal models of Parkinson's and Huntington's diseases.     

Modifications in the responsiveness of rat ventrobasal thalamic neurons at different stages of carrageenin-produced inflammation

The present study was aimed at analyzing the responsiveness of the ventrobasal (VB) thalamic neurons in rats presenting with a hyperalgic carrageenin-produced inflammation. The following were studied: the responses of the same VB neuron, before and 15-145 min after the plantar injection of carrageenin in a part of its receptive field (RF) (acute phase); the responses of VB neurons located in the thalamus contralateral to the hyperalgesic inflamed paw, 24-96 h after the injection (subacute phase); and the effect of a local anesthetic injected in the inflamed paw, and that of an intravenous injection of Aspirin, on neuronal response modifications. Responses of VB neurons initially activated by light tactile stimuli (group 1; n = 4) and by moderate joint stimulation (group 3; n = 4) were not modified in the early period following the carrageenin injection. By contrast, in the first few minutes following the injection. VB neurons exclusively driven by noxious mechanical and thermal stimuli (group 2; n = 23), exhibited a clear enhancement of their responses, which persisted during the observation period. These modifications were also observed for responses obtained from part of the RF remote from the injection site; moreover there was an extension of the RF to areas distant from the injured paw. The local injection of an anesthetic (Xylocaine) in this paw, suppressed the modifications of responses of group 2 neurons, elicited not only from the injected paw, but also from the remote parts of the RF. At this time Aspirin was almost inefficient (even at the dose of 100 mg/kg) on responses of these group 2 neurons. In the subacute phase responses of 72 somatosensory neurons were analyzed. Twenty-five of 72 responded to rapid repetitive light tactile stimulation applied on a small contralateral RF (group 1); their responses were similar to those encountered in a normal situation. Thirty-three of 72 neurons responded to intense mechanical stimuli such as pinches (group 2). For half of them the response characteristics were similar to those described in the normal rat; for the other half responses appeared 'faded': short duration; absence of after-discharge; poor reproducibility. Fourteen of 72 neurons responded to moderate stimulation of the joints, deep tissues and/or surrounding cutaneous areas of the inflamed paw (group 3). Their RF was mostly unilateral, i.e. contralateral to the recording site; the responses were sustained during the stimulation but rarely exhibited after-discharge.(ABSTRACT TRUNCATED AT 400 WORDS)     

Dorsolateral funiculus-lesions unmask inhibitory or disfacilitatory mechanisms which modulate the effects of innocuous mechanical stimulation on spinal Fos expression after inflammation

To examine the contribution of low threshold mechanoreceptive afferent input to the development of allodynia and the involvement of descending pathways, we investigated the effects of repeated innocuous brush on inflammation-induced spinal Fos protein expression in dorsolateral funiculus-lesioned (DLFX) rats following hindpaw inflammation. In DLF sham-operated animals, brush stimuli induced a significant increase in the number of Fos-labeled neurons in ipsilateral laminae I–IV, and a slight suppression of Fos expression in ipsilateral laminae V–VI when compared to sham-lesioned rats without brushing. In rats receiving DLFX, the brush-induced increase in Fos expression in laminae I–IV was significantly reduced. The DLFX also unmasked a brush-induced suppression of laminae VII–VIII neurons. These results suggest that innocuous mechanical stimulation of an inflamed hindpaw gives rise to further facilitation of neuronal activity in laminae I–IV and inhibition of neuronal activity in laminae V–VIII. We propose that there is an unmasking of inhibitory mechanisms or a reduction in descending facilitatory effects after DLFX that alter Fos protein expression produced by innocuous mechanical stimulation.