Collagen type IV-related nephropathies in Portugal: pathogenic COL4A5 mutations and clinical characterization of 22 families.

Alport syndrome (AS) is caused by pathogenic mutations in the genes encoding α3, α4 or α5 chains of collagen IV (COL4A3/COL4A4/COL4A5), resulting in hematuria, chronic renal failure (CRF), sensorineural hearing loss (SNHL) and ocular abnormalities. Mutations in the X-linked COL4A5 gene have been identified in 85% of the families (XLAS). In this study, 22 of 60 probands (37%) of unrelated Portuguese families, with clinical diagnosis of AS and no evidence of autosomal inheritance, had pathogenic COL4A5 mutations detected by Sanger sequencing and/or multiplex-ligation probe amplification, of which 12 (57%) are novel. Males had more severe and earlier renal and extrarenal complications, but microscopic hematuria was a constant finding irrespective of gender. Nonsense and splice site mutations, as well as small and large deletions, were associated with younger age of onset of SNHL in males, and with higher risk of CRF and SNHL in females. Pathogenic COL4A3 or COL4A4 mutations were subsequently identified in more than half of the families without a pathogenic mutation in COL4A5. The lower than expected prevalence of XLAS in Portuguese families warrants the use of next-generation sequencing for simultaneous COL4A3/COL4A4/COL4A5 analysis, as first-tier approach to the genetic diagnosis of collagen type IV-related nephropathies.

Can the dopaminergic-related effects of general anesthetics be linked to mechanisms involved in drug abuse and addiction?

BACKGROUND: General anesthetics (GA) are well known for the ability to induce a state of reversible loss of consciousness and unresponsiveness to painful stimuli. However, evidence from animal models and clinical studies show that GA exposure may induce behavioral changes beyond acute effects. Most research and concerns are focused on changes in cognition and memory. METHODS: We will look at effects of GA on behavior that is mediated by the dopaminergic system. RESULTS: Pharmacological resemblance of GA with drugs of abuse, and the complexity and importance of dopaminergic systems in both reward seeking and addictive illnesses make us believe that it deserves an overview about what is already known and what matters to us as healthcare workers and specifically as anesthesiologists. CONCLUSION: A review of available evidence strongly suggests that there may be a link between the effects of GA on the brain and substance abuse, partly explained by their influence on the dopaminergic system.

Bacteremia due to Campylobacter in renal transplantation: a case report and review of literature.

Campylobacter species are the leading cause of acute bacterial diarrhea in industrialized countries. However, bacteremia is detected in <1% of patients with Campylobacter enteritis and is most likely to occur in patients who are immunocompromised or of older age. To our knowledge, only 2 cases of Campylobacter jejuni bacteremia have been reported in renal transplant recipients (RTRs). We present a case of an RTR with C. jejuni bacteremia presenting as self-limiting diarrhea followed by fever and cellulitis. The patient was successfully treated with a 2-week course of imipenem and developed no other complications. We review all cases of Campylobacter bacteremia in RTRs, and discuss clinical presentation and treatment of this potentially fatal disease.

Decrease in the expression of N-methyl-D-aspartate receptors in the nucleus tractus solitarii induces antinociception and increases blood pressure.

N-methyl-D-aspartate receptors (NMDAR) have a role in cardiovascular control at the nucleus tractus solitarii (NTS), eliciting increases or decreases in blood pressure (BP), depending on the area injected with the agonists. In spite of the association between cardiovascular control and pain modulation, the effects of manipulating NMDAR in pain responses have never been evaluated. In this study, we decreased the expression of NMDAR in the NTS using gene transfer to target receptor subunits and evaluate long-term effects. Seven days after the injection of lentiviral vectors containing the NR1a subunit cDNA of NMDAR, in antisense orientation, into the intermediate NTS of Wistar rats, BP was measured, and the formalin test of nociception was performed. The antisense vector induced a decrease of NR1 expression in the NTS and elicited BP rises and hypoalgesia. Antisense vectors inhibited formalin-evoked c-Fos expression in the spinal cord, indicating decreased nociceptive activity of spinal neurons. Using a time-course approach, we verified that the onset of both the increases in BP and the hypoalgesia was at 4 days after vector injection into the NTS. The injection of NMDA into the NTS reversed the effects of antisense vectors in pain behavioral responses and spinal neuronal activation and decreased BP and heart rate. The present study shows that the NR1 subunit of the NMDAR at the NTS is critical in the regulation of tonic cardiovascular and nociceptive control and shows an involvement of the nucleus in the modulation of sustained pain.

α-Lipoic acid normalizes nociceptive neuronal activity at the spinal cord of diabetic rats.

AIM: To evaluate the effects of antioxidant treatment of streptozotocin (STZ)-diabetic rats with α-lipoic acid (α-LA) in neuronal and microglial activation at the spinal cord, an important relay station of nociceptive transmission. Because of the role of the potassium chloride co-transporter 2 (KCC2) in neuronal activation at the spinal cord and the influence of microglia in KCC2 expression, we also evaluated the effects of α-LA in KCC2 expression at the spinal cord. METHODS: Four weeks after STZ injection, the rats received daily intraperitoneal injections of α-LA (100 mg/kg), during 2 weeks. Mechanical nociception was evaluated before and after α-LA treatment. Spinal cords were immunoreacted against 8-OH-dG (marker of oxidative stress damage), Fos (marker of neuronal activation) and CD11b (marker of microglia). KCC2 expression was evaluated by immunohistochemistry and western blotting. RESULTS: Treatment with α-LA decreased the 8-OH-dG and Fos expressions to controls' levels, but did not affect CD11b. Treatment with α-LA alleviated mechanical hyperalgesia and partially corrected KCC2 expression. CONCLUSIONS: This study shows that neuronal hyperactivity at the spinal cord of STZ-diabetic rats can be corrected by α-LA, which may account for alleviation of mechanical hyperalgesia. These effects are probably partially mediated by KCC2, but are independent from microglia.

Minocycline completely reverses mechanical hyperalgesia in diabetic rats through microglia-induced changes in the expression of the potassium chloride co-transporter 2 (KCC2) at the spinal cord.

AIM: neuronal hyperactivity at the spinal cord during mechanical hyperalgesia induced by diabetes may result from a decrease in the local expression of the potassium chloride co-transporter 2 (KCC2), which shifts the action of the neurotransmitter γ-amminobutiric acid (GABA) from inhibitory to excitatory. In this study, we evaluated the effects of spinal microglia inhibition or brain-derived neurotrophic factor (BDNF) blockade on KCC2 expression, spinal neuronal activity and mechanically induced pain responses of streptozotocin (STZ)-diabetic rats. METHODS: four weeks after induction of diabetes, the STZ-diabetic rats received daily intrathecal injections, for 3 days, of minocycline (microglia inhibitor), TrkB/Fc (BDNF sequester) or saline. Behavioural responses to mechanical nociceptive stimulation of STZ-diabetic rats were evaluated by the Randall-Selitto test. The lumbar spinal cord was immunoreacted against the Fos protein (marker of neuronal activation) or KCC2, which was also quantified by western blotting. BDNF levels at the spinal cord were quantified by an enzyme-linked immunosorbent assay (ELISA). RESULTS: minocycline treatment reversed the mechanical hyperalgesia, increased Fos expression and decreased the KCC2 expression detected in STZ-diabetic rats to control levels. Treatment with TrkB/Fc was less effective, inducing moderate effects in mechanical hyperalgesia and Fos expression and only a partial correction of KCC2 expression. BDNF levels were not increased in STZ-diabetic rats. CONCLUSIONS: this study demonstrates that the microglial activation at the spinal cord contributes to mechanical hyperalgesia and spinal neuronal hyperactivity induced by diabetes, apparently by regulating the KCC2 expression. These effects do not seem to be mediated by BDNF, which is an important difference from other chronic pain conditions. New targets directed to prevent spinal microglia activation should be considered for the treatment of mechanical hyperalgesia induced by diabetes.

Low-back pain in HTLV-I-associated myelopathy/tropical spastic paraparesis: nociceptive or neuropathic?

STUDY DESIGN: Cross-sectional. OBJECTIVES: To describe characteristics of low-back pain in human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients and to identify its neuropathic and/or non-neuropathic pain components. SETTING: A reference center for the care of patients with HAM/TSP in Rio de Janeiro, Brazil. METHODS: A total of 90 patients with HAM/TSP referred by tertiary care centers were consecutively assessed. The patients were submitted to a clinical protocol that included Visual Analogue Scale (VAS), Timed Up and Go Test, Bodily Pain Domain of the Short Form 36 Health Status Questionnaire, Douleur Neuropathique 4 Questions (Neuropathic Pain 4 Questions) (DN4) and McGill Pain Questionnaire. RESULTS: The prevalence of low-back pain in the studied sample was 75.5%; pain interferes with physical functioning and worsens with movement and physical effort. It can be relieved by analgesics and rest. Average pain intensity was 51.2 mm on VAS and 1.72 on DN4. The most frequent words used to describe low-back pain were throbbing, burning, jumping and aching. Surprisingly, 32.4% patients pointed the lower extremities as the most painful and used different descriptors. The most common drugs used were analgesics, nonsteroidal anti-inflammatory drugs and tricyclic antidepressants. CONCLUSIONS: Low-back pain in HAM/TSP patients has mainly nociceptive characteristics. Conversely, descriptors for lower extremities pain suggest a neuropathic origin.

Descending control of nociception: Specificity, recruitment and plasticity.

The dorsal horn of the spinal cord is the location of the first synapse in pain pathways, and as such, offers a very powerful target for regulation of nociceptive transmission by both local segmental and supraspinal mechanisms. Descending control of spinal nociception originates from many brain regions and plays a critical role in determining the experience of both acute and chronic pain. The earlier concept of descending control as an "analgesia system" is now being replaced with a more nuanced model in which pain input is prioritized relative to other competing behavioral needs and homeostatic demands. Descending control arises from a number of supraspinal sites, including the midline periaqueductal gray-rostral ventromedial medulla (PAG-RVM) system, and the more lateral and caudal dorsal reticular nucleus (DRt) and ventrolateral medulla (VLM). Inhibitory control from the PAG-RVM system preferentially suppresses nociceptive inputs mediated by C-fibers, preserving sensory-discriminative information conveyed by more rapidly conducting A-fibers. Analysis of the circuitry within the RVM reveals that the neural basis for bidirectional control from the midline system is two populations of neurons, ON-cells and OFF-cells, that are differentially recruited by higher structures important in fear, illness and psychological stress to enhance or inhibit pain. Dynamic shifts in the balance between pain inhibiting and facilitating outflows from the brainstem play a role in setting the gain of nociceptive processing as dictated by behavioral priorities, but are also likely to contribute to pathological pain states.

Microinjection of angiotensin II in the caudal ventrolateral medulla induces hyperalgesia.

Nociceptive transmission from the spinal cord is controlled by supraspinal pain modulating systems that include the caudal ventrolateral medulla (CVLM). The neuropeptide angiotensin II (Ang II) has multiple effects in the CNS and at the medulla oblongata. Here we evaluated the expression of angiotensin type 1 (AT(1)) receptors in spinally-projecting CVLM neurons, and tested the effect of direct application of exogenous Ang II in the CVLM on nociceptive behaviors. Although AT(1)-immunoreactive neurons occurred in the CVLM, only 3% of AT(1)-positive neurons were found to project to the dorsal horn, using double-immunodetection of the retrograde tracer cholera toxin subunit B. In behavioral studies, administration of Ang II (100 pmol) in the CVLM gave rise to hyperalgesia in both the tail-flick and formalin tests. This hyperalgesia was significantly attenuated by local administration of the AT(1) antagonist losartan. The present study demonstrates that Ang II can act on AT(1) receptors in the CVLM to modulate nociception. The effect on spinal nociceptive processing is likely indirect, since few AT(1)-expressing CVLM neurons were found to project to the spinal cord. The renin-angiotensin system may also play a role in other supraspinal areas implicated in pain modulation.

Dynamic of migration of HSV-1 from a medullary pronociceptive centre: antinociception by overexpression of the preproenkephalin transgene.

Herpes Simplex Virus type 1 (HSV-1) vectors are known to inhibit nociceptive transmission at the spinal cord after peripheral applications. Similar approaches may also be useful when applied at the supraspinal pain control system as the system includes pronociceptive (facilitatory) components. We performed a study aimed to analyse the migration of HSV-1 along with the inhibition of pronociception from the medullary dorsal reticular nucleus (DRt), a major facilitatory component of the supraspinal pain control system. To study the migration, a HSV-1 vector expressing lacZ under control of the human cytomegalovirus (hCMV) promoter was injected in the DRt and the expression of beta-galactosidase (beta-gal) was detected at 2, 4, 7, 10 and 14 days. Numerous beta-gal-immunoreactive neurons were observed at the injection site until day 4, and at some of the brain areas projecting to the DRt until day 7. To block the pronociceptive effects of the DRt, a HSV-1 vector expressing the preproenkephalin transgene, under the control of hCMV promoter, was injected into the DRt. Behavioural evaluation was performed at the time-points referred above, using the paw withdrawal latency test to evaluate thermal nociceptive responses. Anti-hyperalgesic effects persisted during 4 days, decreasing after that time-point. The present study demonstrates that selective migration of HSV-1 should be considered in gene therapy strategies based on HSV-1 injections into the brain. The study also shows that it is possible to decrease pain facilitation from the brain using opioidergic inhibition of pronociceptive supraspinal areas.

Neuronal activation at the spinal cord and medullary pain control centers after joint stimulation: a c-fos study in acute and chronic articular inflammation.

Chronic inflammatory pain induces short- and long-term central changes, which have been mainly studied at the spinal cord level. Supraspinal pain control centers intrinsically connected with the dorsal horn are also prone to be affected by chronic inflammatory pain. C-fos expression was used as a neuronal activation marker at spinal and supraspinal levels to i) compare acute and chronic articular inflammation, and ii) analyze the effects of brief innocuous or noxious stimulation of a chronically inflamed joint. Acute articular inflammation was induced by an inflammatory soup with prostaglandin E(2) and bradykinin, both at 10(-5) M. Chronic articular inflammation consisted of 14 days of monoarthritis. Early c-fos expression was studied 4 min after inflammatory soup injection or stimulation of the arthritic joint whereas late c-fos expression was evaluated 2 h after those stimuli. At the spinal cord, the analysis was focused on the dorsal horn (laminae I-V) and supraspinally, five major regions of the endogenous pain control system were considered: the caudal ventrolateral medulla (VLM), the dorsal reticular nucleus (DRt), the ventral reticular nucleus (VRt), the nucleus of the solitary tract (Sol) and the rostroventromedial medulla (RVM). Acute articular inflammation induced early and late increases in c-fos expression at the spinal level and late increases supraspinally whereas the effects of monoarthritis were more moderate and restricted to the spinal cord. When monoarthritic animals were subjected to gentle touch or bending of the joint, early increases in c-fos expression were detected supraspinally, but not at the spinal level. In this region, noxious mechanical stimulation induced late increases in non-inflamed animals and both early and late increases in monoarthritic rats. Supraspinally, noxious stimulation induced only late increases in c-fos expression. The present results show complex differences in the patterns of c-fos expression between the spinal cord and medullary areas of the pain control system during articular inflammation, which indicate that the somatosensory system is differentially affected by the installation of chronic pain.

Secondary hyperalgesia in the monoarthritic rat is mediated by GABAB and NK1 receptors of spinal dorsal horn neurons: a behavior and c-fos study.

Secondary hyperalgesia in the monoarthritic rat is accompanied by a decrease in nociceptive activation of spinal neurons expressing GABA(B) receptors and by the opposite effect in the cells expressing neurokinin 1 (NK1)-receptors. In order to ascertain the relative role of each receptor, the effects of intrathecal administration of SP-saporin (SP-SAP), baclofen or both were evaluated, using a model of secondary hyperalgesia that consists of mechanical stimulation of the hindlimb skin close to an inflamed joint. Four days after the induction of monoarthritis by intraarticular injection of Complete Freund's Adjuvant (CFA), a cannula was implanted at T(13)-L(1) level and 10 microl of saline or SP-SAP (10(-6) M) were intrathecally (i.t.) injected. Fourteen days after CFA-injection, half of the animals from each group received i.t. injections of 10 microl saline and the remainder were injected with the same volume of baclofen (1 microg). Ten minutes later, the animals were behaviorally evaluated by the von Frey test or submitted to noxious mechanical stimulation to analyze c-fos expression. The von Frey thresholds increased after the treatments, but more pronouncedly after baclofen or SP-SAP plus baclofen. In segments L(2)-L(3), the spinal area that receives input from the stimulated skin close to the inflamed joint, the numbers of Fos-immunoreactive neurons were reduced after the three treatments both in the superficial and deep dorsal horn. In segments T(13)-L(1), the numbers of Fos-immunoreactive neurons were significantly reduced after treatment with SP-SAP plus baclofen in both dorsal horn regions, and in the deep dorsal horn after baclofen treatment. We conclude that both GABA(B) and NK1 receptors of spinal dorsal horn neurons participate in secondary hyperalgesia in the monoarthritic rat, although the decrease in GABA inhibition appears to play a more important role than the increase in SP-mediated effects.

Differential expression of NK1 and GABAB receptors in spinal neurones projecting to antinociceptive or pronociceptive medullary centres.

The balance between excitatory and inhibitory input exerted upon spinal cord neurones that belong to spinofugal pathways determines the ultimate type of information transmitted to the brain. We compared the relative expression of NK1 and GABAB receptors in two spinomedullary pathways targeting an antinociceptive area and a pronociceptive centre, respectively, the lateral part of the caudal ventrolateral medulla (VLMlat) and the dorsal reticular nucleus (DRt). Spinal cord sections of rats injected in the VLMlat or DRt with the retrograde tracer cholera toxin subunit B were triple-immunoreacted for the tracer, NK1 receptors and GABAB receptors. The dorsal horn neurones labelled from the VLMlat mainly co-localized the two receptors while those labelled from the DRt mainly expressed GABAB receptors, which was particularly evident in neurones of laminae IV-V. The morphological classification of lamina I neurones projecting to the VLMlat showed that fusiform, flattened and pyramidal cells mainly co-localized NK1 and GABAB receptors. As to lamina I neurones projecting to the DRt, multipolar neurones mainly expressed GABAB receptors while the majority of flattened and pyramidal neurones co-localized NK1 and GABAB receptors. The present results suggest that the expression of NK1 and GABAB receptors varies in neurones participating to different spinofugal pathways. The importance of the present findings in the knowledge of the endogenous supraspinal pain control system is discussed.

Body composition assessed by impedance changes very early with declining renal graft function.

BACKGROUND: Kidney transplant (Tx) restores renal filtration, although it does not achieve the function of two native kidneys, and with time it may variably involute back to chronic renal failure. We hypothesized that bioelectrical impedance analysis (BIA) might highlight differences for body compartments among Tx with different filtration rates, and we compared them with healthy controls. METHODS: 38 Tx patients (25 males, 13 females) were studied at 75.9 +/- 37.8 months postsurgery and divided into three groups: good creatinine clearance (CrCl, ml/min/1.73 m2; > 65.0), borderline (35.0 < CrCl < 60.0) and bad (CrCl < 35.0). BIA was assessed three times in a year. Total body water, extracellular water (ECW), intracellular water (ICW), Na:K exchange rate (Nae:Ke) and phase angle were studied. Healthy (n = 11) and hemodialysis (n = 11) groups were also studied. RESULTS: BIA showed no differences between healthy controls and good Tx while both borderline and bad Tx presented a significantly higher ECW and lower ICW than either good Tx or normal controls. Only good CrCl was different from predialysis. CONCLUSIONS: A good kidney graft manages to restore and maintain normal body composition, even with potential disturbances brought about by steroids and cyclosporine. With mild renal dysfunction a change in body compartments was observed, moving towards the composition of that with chronic renal failure patients.

Effects of prolonged ingestion of epigallocatechin gallate on diabetes type 1-induced vascular modifications in the erectile tissue of rats.

Diabetes Mellitus type 1 is a metabolic disease that predisposes to erectile dysfunction, partly owing to structural and molecular changes in the corpus cavernosum (CC) vessels. The aim of this study was to determine the effects of early treatment with the antioxidant epigallocatechin gallate (EGCG) in cavernous diabetes-induced vascular modifications. Diabetes was induced in two groups of young Wistar rats; one group was treated with EGCG for 10 weeks. A reduction in smooth muscle content was observed in the CC of diabetic rats, which was significantly attenuated with EGCG consumption. No differences were observed among groups, neither in the expression of VEGF assayed by western blotting nor in the immunofluorescent labeling of vascular endothelial growth factor (VEGF) and its receptors (VEGFR1 and VEGFR2). VEGFR2 was restricted to the endothelium, whereas VEGF and VEGFR1 co-localized in the smooth muscle layer. With regard to the Angiopoietin/Tie-2 system, no quantitative differences in Angiopoietin 1 were observed among the experimental groups. Ang1 localization was restricted to the smooth muscle layer, and receptor Tie2 and Angiopoietin 2 were both expressed in the endothelium. In brief, our results suggest that EGCG consumption prevented diabetes-induced loss of cavernous smooth muscle but does not affect vascular growth factor expression in young rats.

Endovanilloid control of pain modulation by the rostroventromedial medulla in an animal model of diabetic neuropathy.

The involvement of transient receptor vanilloid type-1 (TRPV1) channels in pain modulation by the brain remains understudied. The rostroventromedial medulla (RVM) plays a key role in conveying to the spinal cord pain modulatory influences triggered in higher brain centres, with co-existence of inhibitory (antinociceptive) and facilitatory (pronociceptive) effects. In spite of some reports of TRPV1 expression in the RVM, it remains unknown if endovanilloid signalling plays a direct role in local pain modulation. Here we used a model of diabetic neuropathy, the streptozotocin (STZ)-diabetic rat, to study the role of endovanilloid signalling in RVM-mediated pain modulation during chronic pain. Four weeks after diabetes induction, the levels of TRPV1 mRNA and fatty acid amide hydrolase (FAAH), a crucial enzyme for endovanilloid catabolism, in the RVM of STZ-diabetic rats were higher than control. The RVM of STZ-diabetic rats presented decreased levels of several TRPV1 endogenous ligands, namely anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). Administration of capsaicin (a TRPV1 agonist) into the RVM decreased nociceptive behavioural responses in the inflammatory phase of the formalin test (phase 2). These findings suggest that diabetic neuropathy induces plastic changes of RVM endovanilloid signalling, indicating that TRPV1 may be a putative target for pain modulation in this chronic pain condition.

Late Allograft Renal Vein Thrombosis Treated With Anticoagulation Alone: A Case Report.

BACKGROUND: Allograft renal vein thrombosis is a rare complication of kidney transplantation. Most cases occur in the first 2 weeks after transplantation, but there are cases described many years after the transplant surgery. Allograft loss is the usual outcome. METHODS: We present a case of a renal transplant recipient with allograft renal vein thrombosis associated with deep venous thrombosis of a lower limb, 9 years after transplantation. He was successfully treated with anticoagulation alone, with recovery of allograft function. RESULTS: The patient was given unfractioned heparin and elastic compression stockings. Five days later, the patient recovered diuresis and hemodialysis treatment was discontinued. Doppler ultrasound was done and revealed partial re-permeabilization of allograft renal vein, with maximal velocity of 15 cm/s. After 30 months of follow-up, the patient was maintained on oral anticoagulation with warfarin, and no thromboembolic or hemorrhagic events were documented. The patient's serum creatinine was stable, between 1.6 and 1.8 mg/dL. CONCLUSIONS: Our patient demonstrated that anticoagulation alone and dialytic support might be able to promote total recovery of allograft function after renal vein thrombosis.

Imbalance between the expression of NK1 and GABAB receptors in nociceptive spinal neurons during secondary hyperalgesia: a c-Fos study in the monoarthritic rat.

The neurochemical changes that operate in nociceptive spinal cord circuits during secondary hyperalgesia are largely unknown, in particular with respect to the balance between excitatory and inhibitory neurotransmission. In this study we evaluated the expression of NK1 and GABA(B) receptors in nociceptive spinal neurons in a model of secondary hyperalgesia consisting of noxious mechanical stimulation of the hindlimb skin close to a joint chronically inflamed by complete Freund's adjuvant. In spinal segments receiving input from that skin area, Fos-immunodetection was combined with immunocytochemistry for NK1 receptors, GABA(B) receptors or both receptors. In control and monoarthritic animals, neurons double-labeled for Fos and each receptor occurred mainly in laminae I and IV-V. In lamina I, the percentage of NK1 neurons expressing Fos was higher in monoarthritics while lower percentages of GABA(B) neurons expressed Fos. The percentage of Fos-positive cells expressing NK1 immunoreaction did not change in monoarthritics but that of Fos cells with GABA(B) immunoreaction was lower in these animals. In laminae IV-V, a large increase in Fos expression was detected in monoarthritic rats but the relative proportions of Fos-positive neurons expressing each receptor were similar in the two groups. Co-localization of NK1 and GABA(B) receptors occurred only in lamina I neurons in both experimental groups with no differences between control and monoarthritic animals in the percentages of Fos-positive neurons that expressed the receptors. Considering the participation of lamina I neurons bearing NK1 and GABA(B) receptors in several spinofugal systems, it is possible that the imbalance between excitatory and inhibitory actions exerted, respectively, by substance P and GABA may subserve secondary hyperalgesia by increasing ascending transmission of nociceptive input.