Biomedical subjects

K Ren

Publications and source records attributed to K Ren.

At least 37 records · Page 2Linked to original sources

PubMed2000

Potent and nontoxic antisense oligonucleotides containing locked nucleic acids.

Insufficient efficacy and/or specificity of antisense oligonucleotides limit their in vivo usefulness. We demonstrate here that a high-affinity DNA analog, locked nucleic acid (LNA), confers several desired properties to antisense agents. Unlike DNA, LNA/DNA copolymers were not degraded readily in blood serum and cell extracts. However, like DNA, the LNA/DNA copolymers were capable of activating RNase H, an important antisense mechanism of action. In contrast to phosphorothioate-containing oligonucleotides, isosequential LNA analogs did not cause detectable toxic reactions in rat brain. LNA/DNA copolymers exhibited potent antisense activity on assay systems as disparate as a G-protein-coupled receptor in living rat brain and an Escherichia coli reporter gene. LNA-containing oligonucleotides will likely be useful for many antisense applications.

Animals↗

PubMed2000

The up-regulation of preprodynorphin mRNA in trigeminoparabrachial neurons after inflammation.

Inflammation of the temporomandibular joint (TMJ) produces an increase in preprodynorphin (PPD) mRNA expression in the spinal trigeminal nucleus (Vsp) and paratrigeminal nucleus (Pa5) of the rat. In this study, we further demonstrated that a portion of the TMJ inflammation-induced PPD mRNA positive neurons in the Vsp and Pa5 projected to the parabrachial nucleus (PB). In inflamed rats, the percentage of trigemino- and paratrigeminoparabrachial neurons with up-regulation of PPD mRNA was significantly increased in the ipsilateral Vsp (5.7+/-1.8%) and Pa5 (22.8+/-7.4%, n = 3) when compared with the contralateral side and with saline-treated controls (p < 0.05). These results suggest that the selective up-regulation of PPD mRNA in the Vsp and Pa5 following TMJ inflammation involves ascending trigeminal nociceptive pathways.

Animals↗

PubMed2000

Enhanced delta-opioid receptor-mediated antinociception in mu-opioid receptor-deficient mice.

Inflammatory hyperalgesia was induced in wild-type, heterozygous and mu-opioid receptor knockout mice after an intraplantar injection of complete Freund's adjuvant. micro-Opioid receptor knockout mice exhibited faster recovery from hyperalgesia as compared to heterozygous (P<0.05) and wild-type (P<0.01) mice. Naloxone restored hyperalgesia in all genotypes. Naltrindole (delta-opioid receptor-selective antagonist) partially restored the hyperalgesia only in mu-opioid receptor knockout mice (P<0.001). Nor-binaltorphimine (kappa-opioid receptor-selective antagonist) had no effect. The mu-opioid receptor-selective agonist, [D-Ala(2), MePhe(4),Gly-ol(5)]enkephalin (DAMGO), reduced the hyperalgesia in heterozygous and wild-type but not in mu-opioid receptor knockout mice while U69,593 ¿(+)-(5alpha,7alpha, 8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4. 5]dec-8-yl]-benzeneacetamide, kappa-opioid receptor-selective¿ produced similar effects in all mice. The delta-opioid receptor-selective agonists, [D-Pen(2), D-Pen(5)]enkephalin (DPDPE) and deltorphin ([D-Ala(2)]deltrophin-II), produced significantly greater antihyperalgesia in knockout mice (P<0.05). The findings suggest that mu-opioid receptors may be involved in the persistence of inflammatory hyperalgesia and that a delta-opioid receptor-mediated compensatory mechanism in the absence of the mu-opioid receptor is activated by persistent hyperalgesia.

Analgesia↗

PubMed2000

Insulin increases leptin mRNA expression in abdominal subcutaneous adipose tissue in humans.

Insulin regulates expression and production of leptin in rodents but whether this is also true in humans remains unclear. To test the effects of acute hyperinsulinemia on expression of leptin mRNA in humans, percutaneous needle biopsies of abdominal subcutaneous adipose tissue were performed at baseline and immediately following a 200-min two-step hyperinsulinemic-euglycemic glucose clamp in 16 Pima Indians (8M/8F). Leptin mRNA was quantified by reverse transcription, PCR amplification and expressed relative to actin mRNA. Leptin mRNA levels were higher in women than men (25.6 +/- 1.7 v 16.9 +/- 2.1 relative units, P = 0.003) at baseline. Baseline levels were directly related to percentage body fat (r = 0.54, P = 0. 03) and fasting plasma glucose concentrations (r = 0.57, P = 0.02) and were negatively correlated to glucose disposal at physiologic insulin concentrations (750 +/- 40 pmol/L) during the clamp (r = -0. 51, P = 0.04). Acute hyperinsulinemia (final insulin concentration 11560 +/- 950 pmol/L) increased leptin mRNA levels in 13 of 16 individuals an average of 13% (21.3 +/- 1.7 to 24.2 +/- 1.2 relative units, P = 0.01). Changes in leptin mRNA were directly related to glucose disposal rates during physiologic hyperinsulinemia (r = 0.54, P < 0.04). These results suggest that the expression of leptin mRNA is regulated by insulin in humans, as it is in rodents.

Abdomen↗

PubMed2000

Differential effects of spinal (R)-ketoprofen and (S)-ketoprofen against signs of neuropathic pain and tonic nociception: evidence for a novel mechanism of action of (R)-ketoprofen against tactile allodynia.

The spinal activity of racemic ketoprofen and its enantiomers in models of neuropathic and tonic pain was explored in rats. Tactile allodynia and thermal hyperalgesia were induced by tight ligation of the L(5)/L(6) spinal nerves. Tonic pain was modeled by the formalin-induced flinch response. The spinal injection of (S)-ketoprofen alone or of morphine alone did not produce antiallodynic activity. A 1:1 combination of these drugs produced a robust dose-dependent antiallodynic action, consistent with previous observations where (S)-ketorolac combined with morphine also produced antiallodynia. (R)-ketoprofen given alone spinally produced a dose-dependent antiallodynia, but its activity was not augmented by spinal morphine. Conversely, (S)-ketoprofen, but not (R)-ketoprofen, blocked the second phase of the formalin-induced flinch response; neither enantiomer significantly blocked phase one of the formalin response. Again, (S)-, but not (R)-ketoprofen, interacted synergistically with spinal morphine in suppressing the phase II formalin response. These results are consistent with a spinal COX inhibitory action of (S)-ketoprofen. These results also point to a novel, as yet undefined, mechanism of action of (R)-ketoprofen against signs of neuropathic pain that does not appear to involve COX inhibition. The ability to modulate tactile allodynia is of special interest as this represents an aspect of clinical neuropathic pain that is very difficult to treat adequately.

Analgesics, Opioid↗

PubMed2000

Dorsal column-thalamic pathway is involved in thalamic hyperexcitability following peripheral nerve injury: a lesion study in rats with experimental mononeuropathy.

A total of 68 neurons were recorded from the ventro-postero-lateral nucleus of thalamus (VPL) in rats with a unilateral chronic constriction injury (CCI) of the sciatic nerve (n=20), sham operation (n=24) and naive rats (n=24), and effects of the lesion of dorsal column (DC) pathway [DC lesion or DC+gracile nucleus lesions] on VPL nucleus neuronal activities were studied. In the VPL nucleus contralateral to the CCI (receiving input from the injured nerve), response latencies of low threshold mechanoreceptive (LTM) and wide dynamic range (WDR) neurons to electrical stimulation of the sciatic nerve were significantly longer than that in the contralateral VPL nucleus receiving input from the sham-operated side (P<0.05). In contrast, response latencies of LTM and WDR neurons to DC stimulation were not different between the sham operated and CCI sides (0.05). Background activity of WDR neurons was significantly higher in the VPL nucleus contralateral to the CCI side when compared to neurons in the VPL nucleus contralateral to the sham operated side and in naive animals. Responses of LTM and WDR neurons to innocuous mechanical stimulation of the receptive fields were significantly decreased after DC and DC+gracile nucleus lesions in all animals. However, the responses of WDR neurons to noxious stimuli were selectively reduced only in rats with CCI by DC and DC+gracile nucleus lesions (P<0.05). The decrease in noxious stimulus-evoked responses of WDR neurons in the VPL nucleus contralateral to the CCI side after DC and DC+gracile nucleus lesions was greater than that in the VPL nucleus contralateral to the sham operated side and naive animals. These results indicated that DC and DC+gracile nucleus lesions produced selective and stronger effect on noxious responses of VPL nucleus WDR neurons receiving input from the site of nerve injury. The findings suggest that the gracile nucleus-thalamic pathway conveys, or modulates, nociceptive information to the VPL nucleus following peripheral nerve injury, resulting in an increase in VPL nucleus response to noxious stimuli that contributes to the development of mechanical hyperalgesia.

Animals↗

PubMed1999

Masseteric inflammation-induced Fos protein expression in the trigeminal interpolaris/caudalis transition zone: contribution of somatosensory-vagal-adrenal integration.

The effects of vagotomy and adrenalectomy on the expression of Fos protein in brainstem neurons following the inflammation of masseter muscle were examined in order to differentiate the Fos activation related to nociceptive processing in contrast to that due to somatoautonomic processing. The inflammation was induced by a unilateral injection of complete Freund's adjuvant (CFA) into the masseter muscle under methohexital anesthesia after a small skin-cut (S-cut). After the CFA injection, Fos positive neurons were identified in bilateral spinal trigeminal nucleus (VSP), nucleus tractus solitarius (NTS), ventrolateral medulla (VLM) and inferior medial olivary nucleus (IOM). At the level of the trigeminal subnucleus interpolaris/caudalis (Vi/Vc) transition zone, there was a selective induction of Fos-like immunoreactivity (LI) in the VSP and NTS, when compared to control rats (anesthesia with or without S-cut). A major portion of the Fos-LI in the VSP at the level of the caudal Vc was apparently activated by S-cut. Bilateral adrenalectomy or a unilateral vagotomy resulted in a selective reduction of inflammation-induced Fos-LI in the VSP at the Vi/Vc transition zone (P<0.05) and NTS (P<0.05), but had less effect on Fos-LI in the caudal Vc. These results suggest that the inflammation of the masseter muscle, an injury of orofacial deep tissue, results in a widespread change in neuronal activity in the VSP and NTS that depends in part on the integrity of the adrenal cortex and vagus. Thus, in addition to somatotopically organized nociceptive responses, orofacial deep tissue injury also is coupled to somatovisceral and somatoautonomic processing that contribute to central neural activation.

Adrenal Glands↗

PubMed1999

Persistent Fos protein expression after orofacial deep or cutaneous tissue inflammation in rats: implications for persistent orofacial pain.

This study was designed to systematically examine the effects of persistent orofacial tissue injury on prolonged neuronal activation in the trigeminal nociceptive pathways by directly comparing the effects of orofacial deep vs. cutaneous tissue inflammation on brainstem Fos protein expression, a marker of neuronal activation. Complete Freund's adjuvant (CFA) was injected unilaterally into the rat temporomandibular joint (TMJ) or perioral (PO) skin to produce inflammation in deep or cutaneous tissues, respectively. Rats were perfused 2 hours, 24 hours, 3 days, or 10 days following CFA injection. The TMJ and PO inflammation-induced Fos expression paralleled the intensity and course of inflammation over the 10-day observation period, suggesting that the increase in intensities and persistence of Fos protein expression may be associated with a maintained increase in peripheral input. Compared to PO CFA injection, the injection of CFA into the TMJ produced a significantly stronger inflammation associated with a greater Fos expression. In TMJ- but not in PO-inflamed rats, Fos-like immunoreactivity (LI) spread from superficial to deep upper cervical dorsal horn as the inflammation persisted and there was a dominant ipsilateral Fos-labeling in the paratrigeminal nucleus. Common to TMJ and PO inflammation, Fos-LI was induced in the trigeminal subnuclei interpolaris and caudalis, C1-2 dorsal horn, and other medullary nuclei. Substantial bilateral Fos-LI was found in the interpolaris-caudalis trigeminal transition zone. Further analysis revealed that Fos-LI in the ventral transition zone was equivalent bilaterally, whereas Fos-LI in the dorsal transition zone was predominantly ipsilateral to the inflammation. The differential induction of Fos expression suggests that an increase in TMJ C-fiber input after inflammation and robust central neuronal hyperexcitability contribute to persistent pain associated with temporomandibular disorders.

Animals↗

PubMed1999

Laminar-selective noradrenergic and serotoninergic modulation includes spinoparabrachial cells after inflammation.

We evaluated the effects of chemical lesions on hindpaw inflammation-induced Fos protein expression in spinoparabrachial neurons that were retrogradely labeled by Fluoro-Gold. The descending serotoninergic and noradrenergic pathways were destroyed by the selective neurotoxins, 5,7-DHT and DSP-4, respectively. After 5,7-DHT treatment there was a significant increase in double-labeled neurons only in the lateral reticulated neck of the dorsal horn 24h after inflammation compared with vehicle-injected controls. In contrast, the DSP-4 treatment resulted in a more robust increase in double-labeled neurons in the ipsilateral superficial dorsal horn than in the neck of the dorsal horn. These results indicate that after inflammation the enhanced modulation from descending serotoninergic and noradrenergic pathways targets supraspinally projecting neurons to dampen increased ascending nociceptive input. Further, these pathways differentially suppress the responses of spinoparabrachial neurons in the deep and superficial dorsal horn.

5,7-Dihydroxytryptamine↗

PubMed1999

Orofacial deep and cutaneous tissue inflammation differentially upregulates preprodynorphin mRNA in the trigeminal and paratrigeminal nuclei of the rat.

Preprodynorphin (PPD) and preproenkephalin (PPE) gene expression in a rat model of orofacial inflammation were examined in order to further characterize the neurochemical mechanisms underlying orofacial inflammation and hyperalgesia. Deep and cutaneous orofacial inflammation was produced by a unilateral injection of complete Freund's adjuvant (CFA) into the rat temporomandibular joint (TMJ) or perioral skin (PO), respectively. RNA blot analysis of the tissues including the spinal trigeminal complex revealed that the PPD mRNA level ipsilateral to TMJ inflammation was increased by 56.5+/-14.7% (n=4) when compared to the Naive group, and was significantly greater than the contralateral PPD mRNA level (p<0.05). The distribution of neurons that exhibited PPD mRNA after inflammation was localized by in situ hybridization (naive approximately 0). In TMJ-inflamed rats (n=6) PPD mRNA-positive neurons were found ipsilaterally in the medial portion of laminae I-II of the upper cervical dorsal horn (4.5+/-0.3), the dorsal portion of the subnucleus caudalis and caudal subnucleus interpolaris (5.2+/-0.3), and the paratrigeminal nucleus (6.4+/-1.2). A very localized induction of PPD mRNA was also identified in a group of neurons in the intermediate portion of the subnucleus caudalis (2.4+/-0.4) in PO-inflamed rats (n=6). The distribution of these PPD mRNA-positive neurons was somatotopically relevant to the site of injury. There were no significant changes in PPE mRNA expression in both TMJ- and PO-inflamed rats. These results indicate that TMJ inflammation resulted in a more intense and widespread increase in PPD mRNA expression when compared to PO inflammation. These changes may contribute to persistent central hyperexcitability and pain associated with temporomandibular disorders.

Animals↗

PubMed1999

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.

Animals↗

PubMed1999

An improved method for assessing mechanical allodynia in the rat.

A method has been developed for assessing mechanical nociceptive threshold and allodynia in the rat. The animal was habituated to stand on its hind paws while leaning against an experimenter's hand. The rat was unrestrained, but remained in the position throughout the test session. The Semmes-Weinstein monofilaments were used to probe body areas such as the lateral edge of the hind paw and the orofacial skin. The median withdrawal response threshold was found to be 62.9 g for both hind paws (95 % confidence interval, CL, 61.4-66.7 g, n = 69). The median response thresholds of the orofacial skin were 62.9 g (95% CL: 55.7-68.7 g, n = 45), and 25.6 g (95% CL: 22.6-36.3 g, n = 45), for the skin above the temporomandibular joint (PT) and the perioral (PO) skin, respectively. The injection of an inflammatory agent, complete Freund's adjuvant, into the hind paw, peritemporomandibular joint tissue (PTMJ), or PO skin resulted in significant mechanical allodynia. The median response thresholds were reduced to 0.09 g (p < 0.01, n = 6), 5.60 g (p < 0.001, n = 9), and 3.24 g (p < 0.001, n = 9), after hind paw, PTMJ, and PO inflammation, respectively. The allodynia persisted for at least 2 weeks in all cases. This testing paradigm eliminates confounding factors related to weight bearing, and offers a simple, objective, and reliable approach to assess mechanical sensitivity in rats. The method will be useful for studying the central mechanisms of mechanical allodynia. Importantly, this method can also be used in the orofacial region, and will facilitate studies on the mechanisms of persistent orofacial pain in animals.

Animals↗

PubMed1999

Nucleus reticularis gigantocellularis and nucleus raphe magnus in the brain stem exert opposite effects on behavioral hyperalgesia and spinal Fos protein expression after peripheral inflammation.

Previous findings indicate that the brain stem descending system becomes more active in modulating spinal nociceptive processes during the development of persistent pain. The present study further identified the supraspinal sites that mediate enhanced descending modulation of behavior hyperalgesia and dorsal horn hyperexcitability (as measured by Fos-like immunoreactivity) produced by subcutaneous complete Freund's adjuvant (CFA). Selective chemical lesions were produced in the nucleus raphe magnus (NRM), the nuclei reticularis gigantocellularis (NGC), or the locus coeruleus/subcoeruleus (LC/SC). Compared to vehicle-injected animals with injection of vehicle alone, microinjection of a serotoninergic neurotoxin 5,7-dihydroxytryptamine into the NRM significantly increased thermal hyperalgesia and Fos protein expression in lumbar spinal cord after hindpaw inflammation. In contrast, the selective bilateral destruction of the NGC with a soma-selective excitotoxic neurotoxin, ibotenic acid, led to an attenuation of hyperalgesia and a reduction of inflammation-induced spinal Fos expression. Furthermore, if the NGC lesion was extended to involve the NRM, the behavioral hyperalgesia and CFA-induced Fos expression were similar to that in vehicle-injected rats. Bilateral LC/SC lesions were produced by microinjections of a noradrenergic neurotoxin, DSP-4. There was a significant increase in inflammation-induced spinal Fos expression, especially in the ipsilateral superficial dorsal horn following LC/SC lesions. These results demonstrated that multiple specific brain stem sites are involved in descending modulation of inflammatory hyperalgesia. Both NRM and LC/SC descending pathways are major sources of enhanced inhibitory modulation in inflamed animals. The persistent hyperalgesia and neuronal hyperexcitability may be mediated in part by a descending pain facilitatory system involving NGC. Thus, the intensity of perceived pain and hyperalgesia is fine-tuned by descending pathways. The imbalance of these modulating systems may be one mechanism underlying variability in acute and chronic pain conditions.

5,6-Dihydroxytryptamine↗

PubMed1999

Descending modulation of opioid-containing nociceptive neurons in rats with peripheral inflammation and hyperalgesia.

Inflammation and hyperalgesia induce a dramatic up-regulation of opioid messenger RNA and peptide levels in nociceptive neurons of the spinal dorsal horn. Descending axons modulate nociceptive transmission at the spinal level during inflammatory pain, and may play a role in the development of persistent pain. The role of descending bulbospinal pathways in opioid-containing nociceptive neurons was examined. Removal of descending inputs to the spinal cord was performed by complete spinal transection at the midthoracic level. Seven days after spinal transection, rats received a unilateral hindpaw injection of complete Freund's adjuvant, a noxious stimulus that produces inflammation and hyperalgesia. Tissues from the L4 and L5 segments of the spinal cord were removed and analysed by northern blotting and immunocytochemistry. Spinal transection resulted in a further increase in both dynorphin and enkephalin messenger RNA content following complete Freund's adjuvant injection. There was a similar distribution and number of dynorphin-immunoreactive cells in transected rats compared to rats which received sham surgery. These data suggest that increased dynorphin messenger RNA ipsilateral to inflammation, in rats without descending axons, was due to increased expression within the same cells and not to recruitment of additional dynorphin-expressing cells. This reflects a greater dynamic response of nociceptive neurons to noxious stimuli in the absence of descending modulation. Therefore, the net effect of descending afferents on spinal nociceptive circuits may be to reduce the response of opioid-containing neurons to noxious stimulation from the periphery.

Animals↗

PubMed1999

Effects of four herbal extracts on adjuvant-induced inflammation and hyperalgesia in rats.

OBJECTIVE: To evaluate the effects of four herbal medicine extracts on a rat model of inflammatory hyperalgesia. DESIGN/INTERVENTIONS: Inflammation was induced by injecting complete Freund's adjuvant (CFA) into one hindpaw of each rat. Four herbs that are routinely prescribed in Traditional Chinese Medicine for treatment of pain were used: Duhuo (Radix Angelicae Pubescentis), Bai jiang cao (Patriniae Herba cum Radice), Yan hu suo (Rhizoma Corydalis) and Sanqui (Panax Notoginseng). The crude water extracts of the herbs were inected intraperitoneally following a repeated treatment profile. OUTCOME MEASURES: Thermal hyperalgesia was assessed by testing each rat's paw withdrawal response to a noxious thermal stimulus. The magnitude of edema was determined by measuring the maximal thickness of the paw with a caliper. The effect of herb extracts on motor performance was assessed by using an accelerating rotarod test. RESULT: Duhuo, Bai jiang cao, and Yan hu suo significantly attenuated CFA-induced hyperalgesia at 2 hours and facilitated the recovery from hyperalgesia (p < 0.05), when compared to saline-treated rats. The CFA-induced edema was reduced by Duhuo at 24 hours, 72 hours and 168 hours; Bai jiang cao at 24 hours, and Yan hu suo at 24 hours and 168 hours. Sanqi did not produce any significant effect on inflammation and hyperalgesia. The rotarod performance was slightly reduced by Bai jiang cao, Yan hu suo, and Sanqi (p < 0.05) but not by Duhuo treatment. CONCLUSION: The present study identified Duhuo as a selective and effective herbal agent in attenuating persistent hindpaw inflammation and hyperalgesia in rats. These results indicate that some herbal agents may provide an alternative approach to the treatment of persistant inflammatory pain and hyperalgesia.

Animals↗

PubMed1999

Medullary dorsal horn neuronal activity in rats with persistent temporomandibular joint and perioral inflammation.

Studies at spinal levels indicate that peripheral tissue or nerve injury induces a state of hyperexcitability of spinal dorsal horn neurons that participates in the development of persistent pain and hyperalgesia. It has not been demonstrated that persistent injury in the orofacial region leads to a similar state of central hyperexcitability in the trigeminal system. The purpose of the present study was to conduct a parametric analysis of the response properties of nociceptive and nonnociceptive neurons in trigeminal nucleus caudalis (medullary dorsal horn, MDH) in a rat model of persistent orofacial inflammation. Neurons were recorded extracellularly and classified as low-threshold mechanoreceptive (LTM, n = 49), wide dynamic range (WDR, n = 82), and nociceptive-specific (NS, n = 11) neurons according to their response properties to mechanical stimuli applied to their cutaneous receptive fields (RFs). The inflammation was induced 24 h before the recordings by injecting complete Freund's adjuvant (CFA) into the temporomandibular joint (TMJ) capsule or the perioral (PO) skin. The mean areas of the high-threshold RFs of WDR neurons in TMJ (8.66 +/- 0.61 cm(2), n = 25) and PO (5.61 +/- 2.07 cm(2), n = 25) inflamed rats were significantly larger than those in naive rats (1.10 +/- 0. 16 cm(2), n = 32). The mean RF size in TMJ-inflamed rats also was significantly larger than that in PO-inflamed rats (P < 0.01). Furthermore the mean area of the RFs of NS neurons (3.74 +/- 1.44 cm(2), n = 5) was significantly larger in TMJ inflamed rats as compared with naive rats (0.4 +/- 0.09 cm(2), n = 3) (P < 0.05). The background activity in the TMJ- and PO-inflamed rats was generally greater in WDR and NS neurons, but less in LTM neurons, when compared with naive rats. The responses of WDR neurons to noxious mechanical stimuli were increased significantly in TMJ-inflamed rats (P < 0.05) as compared with naive rats. WDR neuronal responses to mechanical stimulation also were increased in PO-inflamed rats but to a lesser extent than in TMJ-inflamed rats. The injection of CFA into the TMJ or PO skin resulted in reduced responses of LTM neurons to mechanical stimuli. The responses of MDH nociceptive neurons to 48-55 degrees C heating were greater in inflamed rats as compared with naive rats. A subpopulation of WDR neurons recorded from TMJ (n = 4 of 10)- or PO (n = 3 of 13)-injected rats responded to cooling in addition to heating of the RFs but did not grade their responses with changes in stimulus intensity. These results indicate that persistent orofacial inflammation produced hyperexcitability of MDH nociceptive neurons. TMJ inflammation resulted in more robust changes in MDH nociceptive neurons as compared with PO inflammation, consistent with previous studies of increased inflammation, increased MDH Fos-protein expression, and increased MDH preprodynorphin mRNA expression in this deep tissue orofacial model of pain and hyperalgesia. The inflammation-induced MDH hyperexcitability may contribute to mechanisms of persistent pain associated with orofacial deep tissue painful conditions.

Animals↗

PubMed1999

Central nervous system plasticity and persistent pain.

Nerve signals arising from sites of tissue or nerve injury lead to long-term changes in the central nervous system and contribute to hyperalgesia and the amplification and persistence of pain. These nociceptor activity-induced changes are referred to as central sensitization. Central sensitization involves an increase in the excitability of medullary and spinal dorsal horn neurons brought about by a cascade of events, including neuronal depolarization, removal of the voltage-dependent magnesium block of the N-methyl-D-aspartate (NMDA) receptor, calcium entry into neurons, phosphorylation of the NMDA receptor, a change in the cell's excitability, and an increase in synaptic strength. These changes also include activation of other ionotropic and metabotropic excitatory amino acid receptors, neuropeptides such as substance P, neurotrophins, and kinases involved in the phosphorylation process. Central sensitization occurs in trigeminal nociceptive pathways, and more robust neuronal hyperexcitability occurs following deep tissue stimulation than following cutaneous stimulation. By means of Fos protein immunocytochemistry, researchers have found that 2 distinct regions are activated: the subnucleus interpolaris/caudalis transition zone (Vi/Vc) and the caudal subnucleus caudalis. The latter exhibits changes very similar to those in the spinal dorsal horn, but the Vi/Vc zone likely is involved in autonomic nervous system processing and activation of the pituitary-adrenal axis. Descending systems are also an important component of the central sensitization process and provide the neural networks by which cognitive, attentional, and motivational aspects of the pain experience modulate pain transmission. These findings of nociceptor activity-induced neuronal plasticity have important clinical implications in the development of new approaches to the management of persistent pain.

Chronic Disease↗

PubMed1998

Inflammation-induced Fos protein expression in the rat spinal cord is enhanced following dorsolateral or ventrolateral funiculus lesions.

Previous studies have shown an enhanced expression of Fos protein-like immunoreactivity in the lumbar spinal cord of rats with complete spinal transection following persistent hindpaw inflammation. To further locate the spinal pathways responsible for these effects, we compared the inflammation-evoked Fos expression in rats with bilateral lesions of the dorsolateral (DLFX) or ventrolateral (VLFX) funiculus, and with rats with a sham operation. The results indicate that the number of Fos-labeled neurons was significantly increased in all laminae of the dorsal horn ipsilateral to the inflamed hindpaw and in contralateral deep dorsal horn in both DLFX and VLFX rats compared to sham-operated rats. Moreover, when comparing DLFX and VLFX rats, in the ipsilateral spinal cord, DLFX resulted in more Fos expression in the deep dorsal horn; in contrast, a larger number of Fos-labeled cells in superficial laminae was observed in VLFX rats. These results suggest that modulatory systems, which descend in both DLF and VLF pathways, mediate the enhanced net descending nociceptive inhibition after persistent inflammation, although the supraspinal sites of origin of each pathway are likely functionally diverse.

Animals↗