Biomedical subjects

Jon D Levine

Publications and source records attributed to Jon D Levine.

At least 37 records · Page 2Linked to original sources

PubMed2005

Fibromyalgia: the nerve of that disease.

Fibromyalgia syndrome (FM) is a common, often debilitating and intractable, chronic, generalized pain condition. The development of effective therapies to treat FM has been hindered by a lack of understanding of fundamental mechanisms in the etiology of FM. In view of prominent characteristics that FM shares with other generalized pain conditions, we suggest that a key mechanism in such disorders may be that of altered activity in the subdiaphragmatic vagus nerve. Specifically, we propose that activity in vagal afferents, arising from the gastrointestinal tract, and sympathoadrenal function mediate a contribution of stress to FM and its strong association with irritable bowel syndrome. An important prediction of the proposed mechanism is that interventions that selectively modulate activity in specific populations of subdiaphragmatic afferents might be used to treat the symptoms of FM and other generalized pain syndromes.

Fibromyalgia↗

PubMed2004

Beta 2-adrenergic receptor regulation of human neutrophil function is sexually dimorphic.

While the mechanisms underlying the marked sexual dimorphism in inflammatory diseases are not well understood, the sexually dimorphic sympathoadrenal axis profoundly affects the inflammatory response. We tested whether adrenergic receptor-mediated activation of human neutrophil function is sexually dimorphic, since neutrophils provide the first line of defense in the inflammatory response. There was a marked sexual dimorphism in beta(2)-adrenergic receptor binding, using the specific beta(2)-adrenergic receptor ligand, [(3)H]-dihydroalprenolol, with almost three times more binding sites on neutrophils from females (20,878 +/- 2470) compared to males (7331 +/- 3179). There was also a marked sexual dimorphism in the effects of isoprenaline, a beta-adrenergic receptor agonist, which increased nondirected locomotion (chemokinesis) in neutrophils obtained from females, while having no effect on neutrophils from males. Isoprenaline stimulated the release of a chemotactic factor from neutrophils obtained from females, but not from males. This chemotactic factor acts on the G protein-coupled CXC chemokine receptor 2 (CXCR2) chemokine receptor, since an anti-CXCR2 antibody and the selective nonpeptide CXCR2 antagonist SB225002, inhibited chemotaxis produced by this factor. While interleukin- (IL-) 8 is a principal CXCR2 ligand, isoprenaline did not produce an increase in IL-8 release from neutrophils. IL-8-induced chemotaxis was inhibited in a sexually dimorphic manner by isoprenaline, which also stimulated release of a mediator from neutrophils that induced chemotaxis, that was inhibited by anti-CXCR2 antibodies. These findings indicate an important role for adrenergic receptors in the modulation of neutrophil trafficking, which could contribute to sex-differences in the inflammatory response.

Adrenergic beta-2 Receptor Agonists↗

PubMed2004

Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat.

The development of treatments for neuropathic pain has been hindered by our limited understanding of the basic mechanisms underlying abnormalities in nociceptor hyperexcitability. We recently showed that the polymodal receptor transient receptor potential vanilloid 4 (TRPV4), a member of the transient receptor potential (TRP) family of ion channels, may play a role in inflammatory pain (Alessandri-Haber et al., 2003). The present study tested whether TRVP4 also contributes to neuropathic pain, using a rat model of Taxol-induced painful peripheral neuropathy. Taxol is the most widely used drug for the treatment of a variety of tumor types, but the dose of Taxol that can be tolerated is limited by the development of a small-fiber painful peripheral neuropathy. We found that Taxol treatment enhanced the nociceptive behavioral responses to both mechanical and hypotonic stimulation of the hind paw. Spinal administration of antisense oligodeoxynucleotides to TRPV4, which reduced the expression of TRPV4 in sensory nerve, abolished Taxol-induced mechanical hyperalgesia and attenuated hypotonic hyperalgesia by 42%. The enhancement of osmotic nociception involves sensitization of osmotransduction in primary afferents because osmotransduction was enhanced in cultured sensory neurons isolated from Taxol-treated rats. Taxol-induced TRPV4-mediated hyperalgesia and the enhanced osmotransduction in cultured nociceptors were dependent on integrin/Src tyrosine kinase signaling. These results suggest that TRPV4 plays a crucial role in a painful peripheral neuropathy, making it a very promising target for the development of a novel class of analgesics.

Animals↗

PubMed2004

Mechanosensitive duodenal afferents contribute to vagal modulation of inflammation in the rat.

Noxious stimuli inhibit inflammation by activating neuroendocrine stress axes, an effect that is potently attenuated by ongoing activity in subdiaphragmatic vagal afferents. Because this vagal afferent activity is carried in the coeliac and coeliac accessory branches of the subdiaphragmatic vagus, we tested the hypothesis that the activity arises from vagal afferents that innervate a proximal segment of the gastrointestinal tract. Surgical removal of the duodenum, but not the stomach, produces a marked (six orders of magnitude) leftward shift in the dose-response curve for intraplantar capsaicin-induced inhibition of synovial plasma extravasation induced by the potent inflammatory mediator bradykinin, in the knee joint; this is similar in magnitude to the inhibition produced by subdiaphragmatic or by coeliac plus coeliac accessory branch vagotomy. Fasting, to unload mechanically sensitive polymodal afferents in the proximal gastrointestinal tract, produces a similar leftward shift in the dose-response curve for the inhibitory effect of capsaicin, an effect that is reversed by balloon distension in the duodenum in fasted rats, while balloon distension postvagotomy had no effect. These results suggest that activation of mechanically sensitive vagal afferents in the duodenum contributes vagal afferent activity that modulates neuroendocrine control of the inflammatory response.

Animals↗

PubMed2004

Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat.

To elucidate the underlying mechanisms involved in AIDS therapy-induced peripheral neuropathy, we have developed a model of nucleoside analog reverse transcriptase inhibitor-induced painful peripheral neuropathy in the rat, using 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI) and 2',3'-didehydro-3'-deoxythymidine (d4T), AIDS chemotherapeutic drugs that are also components of AIDS highly active anti-retroviral therapy. Administration of ddC, ddI and d4T produced dose-dependent mechanical hypersensitivity and allodynia. Peripheral administration of inhibitors of protein kinase A, protein kinase C, protein kinase G, p42/p44-mitogen-activated protein kinase (ERK1/2) and nitric oxide synthase, which have demonstrated anti-hyperalgesic effects in other models of metabolic and toxic painful peripheral neuropathies, had no effect on ddC-, ddI- and d4T-induced hypersensitivity. Since suramin, an anti-parasitic and anti-cancer drug, which shares with the anti-retroviral nucleoside analogs, mitochondrial toxicity, altered regulation of intracellular calcium, and a sensory neuropathy in humans, also produced mechanical hypersensitivity that was not sensitive to the above second messenger inhibitors we evaluated the role of intracellular calcium. Intradermal or spinal injection of intracellular calcium modulators (TMB-8 and Quin-2), which had no effect on nociception in control rats, significantly attenuated and together eliminated ddC and suramin-induced mechanical hypersensitivity. In electrophysiology experiments in ddC-treated rats, C-fibers demonstrated alterations in pattern of firing as indicated by changes in the distribution of interspike intervals to sustained suprathreshold stimuli without change in mechanical activation thresholds or in number of action potentials in response to threshold and suprathreshold stimulation. This study provides evidence for a novel, calcium-dependent, mechanism for neuropathic pain in a model of AIDS therapy-induced painful peripheral neuropathy.

Aminoquinolines↗

PubMed2004

Integrin signaling in inflammatory and neuropathic pain in the rat.

Many painful conditions are associated with alterations in the extracellular matrix (ECM) of affected tissues. While several integrins, the receptors for ECM proteins, are present on sensory neurons that mediate pain, the possible role of these cell adhesion molecules in inflammatory or neuropathic pain has not been explored. We found that the intradermal injection of peptide fragments of domains of laminin and fibronectin important for adhesive signaling selectively inhibited the hyperalgesia caused by prostaglandin E2 (PGE2) and epinephrine (EPI), respectively. The block of EPI hyperalgesia was mimicked by other peptides containing the RGD integrin-binding sequence. Monoclonal antibodies (mAbs) against the alpha1 or alpha3 integrin subunits, which participate in laminin binding, selectively blocked PGE2 hyperalgesia, while a mAb against the alpha5 subunit, which participates in fibronectin binding, blocked only EPI-induced hyperalgesia. A mAb against the beta1 integrin subunit, common to receptors for both laminin and fibronectin, inhibited hyperalgesia caused by both agents, as did the knockdown of beta1 integrin expression by intrathecal injection of antisense oligodeoxynucleotides. The laminin peptide, but not the fibronectin peptides, also reversibly abolished the longer lasting inflammatory hyperalgesia induced by carrageenan. Finally, the neuropathic hyperalgesia caused by systemic administration of the cancer chemotherapy agent taxol was reversibly inhibited by antisense knockdown of beta1 integrin. These results strongly implicate specific integrins in the maintenance of inflammatory and neuropathic hyperalgesia.

Animals↗

PubMed2004

Isolation of an mRNA binding protein homologue that is expressed in nociceptors.

The peripheral detection of painful stimuli requires the activation of small-diameter primary afferent neurons known as nociceptors. We have exploited two features of nociceptor biology, expression of the high affinity receptor for nerve growth factor (TrkA) and sensitivity to capsaicin, to isolate novel proteins using a differential display cloning scheme. A resulting approximately 4.3-kb cDNA was isolated and sequence analysis inferred a approximately 157-kDa protein containing a signal/mitochondrial targeting peptide sequence. Due to its molecular weight and significant amino acid identity with 'human leucine-rich protein 130'[leucine-rich pentatricopeptide motif containing (LRPPRC)], we termed the cDNA candidate leucine-rich protein 157 (rLRP157). Western blot analysis of HEK293 cells over-expressing the candidate cDNA showed a single protein product of similar size to that found in rat dorsal root ganglion as well as in other neuronal tissues and cell lines. Although expressed in a wide variety of tissues, in situ hybridization and immunohistochemistry in dorsal root ganglion revealed that rLRP157 expression was restricted to the small-diameter neurons. Sequence identity with previously characterized mRNA binding proteins and its subcellular localization in sensory neurons suggest that rLRP157 is associated with mitochondrial function. Moreover, the genetic basis of French-Canadian Leigh syndrome, which confers a loss of mitochondrial cytochrome c oxidase and is characterized by neurodegeneration, was recently mapped to a mutation in the LRPPRC gene. Taken together with its expression in small-diameter sensory neurons, we hypothesize that rLRP157, the rat orthologue of the human LRPPRC, may play a role in the modulation of peripheral pain transduction and serve as a novel marker for nociceptor subtypes.

Animals↗

PubMed2004

Caspase signalling in neuropathic and inflammatory pain in the rat.

Whereas small-fibre sensory neuropathies might ultimately lead to cell death and loss of sensation, they first progress through a phase, which might last for years, characterized by the presence of analgesia-resistant neuropathic dysesthesias and pain. Much previous research has addressed these two phases as separate phenomena mediated by presumably discrete biochemical mechanisms. We hypothesized that activity in signalling pathways that ultimately lead to apoptosis plays a critical role in the generation of neuropathic pain, before death of sensory neurons becomes apparent. We have tested the hypothesis that activator and effector caspases, defining components of programmed cell death (apoptosis) signalling pathways, also contribute to pain-related behaviour in animals with small-fibre peripheral neuropathies and that the death receptor ligand, tumour necrosis factor-alpha, and its downstream second messenger, ceramide, also produce pain-related behaviour via this mechanism. In two models of painful peripheral neuropathy, HIV/AIDS therapy (induced by the nucleoside reverse transcriptase inhibitor, dideoxycytidine), and cancer chemotherapy (induced by vincristine) peripheral neuropathy, and for pain-related behaviour induced by tumour necrosis factor-alpha and its second messenger, ceramide, inhibition of both activator (1, 2, 8 and 9) and effector (3) caspases attenuates neuropathic pain-related behaviour, although has no effect in streptozotocin-diabetic neuropathy and control rats. We conclude that during a latent phase, before apoptotic cell death is manifest, the caspase signalling pathway can contribute to pain in small-fibre peripheral neuropathies, and that inflammatory/immune mediators also activate these pathways. This suggests that these pathways are potential targets for novel pharmacological agents for the treatment of inflammatory as well as neuropathic pain.

Animals↗

PubMed2003

Dose ratio is important in maximizing naloxone enhancement of nalbuphine analgesia in humans.

The analgesic effect of kappa partial agonist opioids (i.e. nalbuphine, pentazocine and butorphanol) is significantly greater in women. Recent evidence suggests that this sexual dimorphism may result from a naloxone-sensitive anti-analgesic effect that is activated along with, and summates with, the analgesic effect of these agents, resulting in decreased analgesia or increased pain. For example, nalbuphine (5 mg) produces profound anti-analgesia (i.e. enhanced pain) in men, but addition of a low dose of the opioid receptor antagonist naloxone (0.4 mg, opioid antagonist) induces significant analgesia in men and enhances nalbuphine analgesia in women. To further delineate the dose-dependent relationship of nalbuphine and naloxone, we recently evaluated the effect of a lower dose of nalbuphine (2.5 mg) with and without naloxone (0.4 mg) on dental postoperative pain. In women, nalbuphine alone induced modest short duration analgesia, which was antagonized by the addition of naloxone. In men, this dose of nalbuphine alone did not produce analgesia or anti-analgesia, and naloxone did not alter the response to nalbuphine. Thus, it appeared that the 2.5 mg dose of nalbuphine was not sufficient to induce anti-analgesia while the 0.4 mg dose of naloxone was able to antagonize the analgesic effect of nalbuphine, at least in women. In the current study, we tested the hypothesis that an important determinant of naloxone enhancement of nalbuphine analgesia is the dose ratio of nalbuphine to naloxone. Since a dose ratio of 12.5:1 (i.e. 5 mg nalbuphine:0.4 mg naloxone) resulted in analgesic enhancement, but a dose ratio of 6.25:1 (2.5 mg:0.4 mg) did not, we tested the same, lower, dose of nalbuphine (2.5 mg) in combination with a lower dose of naloxone (0.2 mg) to maintain the 12.5:1 dose ratio. This lower dose of naloxone significantly prolonged the analgesic effect of nalbuphine in both men and women, suggesting that the anti-analgesic effect of nalbuphine is present in both sexes at the 2.5 mg dose and that the dose ratio of nalbuphine to naloxone is an important determinant of the analgesic efficacy of this combination.

Adult↗

PubMed2003

Role of the sensory neuron cytoskeleton in second messenger signaling for inflammatory pain.

Prostaglandin E(2) (PGE(2)) and epinephrine act directly on nociceptors to produce mechanical hyperalgesia through protein kinase A (PKA) alone or through a combination of PKA, protein kinase C epsilon (PKCepsilon), and extracellular signal-regulated kinase (ERK), respectively. Disruptors of the cytoskeleton (microfilaments, microtubules, and intermediate filaments) markedly attenuated the hyperalgesia in rat paws caused by injection of epinephrine or its downstream mediators. In contrast, the hyperalgesia induced by PGE(2) or its mediators was not affected by any of the cytoskeletal disruptors. These effects were mimicked in vitro, as measured by enhancement of the tetrodotoxin-resistant sodium current. When PGE(2) hyperalgesia was shifted to dependence on PKCepsilon and ERK as well as PKA, as when the tissue is "primed" by prior treatment with carrageenan, it too became dependent on an intact cytoskeleton. Thus, inflammatory mediator-induced mechanical hyperalgesia was differentially dependent on the cytoskeleton such that cytoskeletal dependence correlated with mediation by PKCepsilon and ERK.

Animals↗

PubMed2003

Dexamethasone enhances interaction of endogenous annexin 1 with L-selectin and triggers shedding of L-selectin in the monocytic cell line U-937.

(1) L-selectin, constitutively expressed by leukocytes, is involved in the initial binding of leukocytes to activated endothelium. Anti-inflammatory drugs like glucocorticoids can induce shedding of L-selectin, but the mechanism is still unknown. Annexin 1, a protein whose synthesis and externalization/secretion are induced during the inflammatory response, has been proposed as a mediator of the anti-inflammatory actions of glucocorticoids. (2) The monocytic cell line U-937 strongly expresses Annexin 1 after 24 h of phorbol 12-myristate 13-acetate (PMA, 1 nm) treatment and externalizes/releases the protein after additional 16 h of dexamethasone (1 microm) treatment. (3) This study investigated the possible regulation of cell surface L-selectin shedding by endogenous Annexin 1, and its role in glucocorticoid-induced L-selectin shedding in the U-937 cell line. (4) PMA- and dexamethasone treatment-induced L-selectin shedding was potentially mediated by Annexin 1, since neutralizing antibodies against Annexin 1 reduced dexamethasone- and Annexin 1-induced shedding. (5) Immunoprecipitation and binding assays provided support for the suggestion that this effect could be mediated by an interaction between externalized Annexin 1 and L-selectin. Such interaction involved the N-terminal domain of Annexin 1 and was calcium-dependent. Confocal microscopy studies demonstrated increased colocalization of Annexin 1 and L-selectin on the cell surface. (6) Overall, our study provides new insights into the potential role of endogenous ANXA1 as a mediator of dexamethasone-induced L-selectin shedding, which may contribute to the anti-inflammatory activity of glucocorticoids.

Annexin A1↗

PubMed2003

Hypotonicity induces TRPV4-mediated nociception in rat.

We hypothesized that TRPV4, a member of the transient receptor family of ion channels, functions as a sensory transducer for osmotic stimulus-induced nociception. We found that, as expected for a transducer molecule, TRPV4 protein is transported in sensory nerve distally toward the peripheral nerve endings. In vivo single-fiber recordings in rat showed that hypotonic solution activated 54% of C-fibers, an effect enhanced by the hyperalgesic inflammatory mediator prostaglandin E2. This osmotransduction causes nociception, since administration of a small osmotic stimulus into skin sensitized by PGE2 produced pain-related behavior. Antisense-induced decrease in expression of TRPV4 confirmed that the channel is required for hypotonic stimulus-induced nociception. Thus, we conclude that TRPV4 can function as an osmo-transducer in primary afferent nociceptive nerve fibers. Because this action is enhanced by an inflammatory mediator, TRPV4 may be important in pathological states and may be an attractive pharmacological target for the development of novel analgesics.

Afferent Pathways↗

PubMed2003

Absence of nalbuphine anti-analgesia in the rat.

In humans, kappa agonist-antagonist opioids such as nalbuphine have been proposed to produce both analgesia and anti-analgesia by acting at distinct receptors. The anti-analgesia appears to be greater in men, which may contribute to the greater nalbuphine analgesia observed in women. Kappa agonist-antagonists are also known to produce sexually dimorphic antinociception in nonhuman species but are generally more potent in males; anti-analgesia has not been reported in animals. The aim of the present study was to determine if nalbuphine anti-analgesia can be detected in the rat. Since nalbuphine anti-analgesia is more sensitive to naloxone antagonism than its analgesic effect, low doses of naloxone were combined with nalbuphine. Using the Randall-Selitto paw-withdrawal test, nalbuphine (0.5-10 mg/kg) induced dose-dependent antinociception in the rat. The antinociceptive effect of nalbuphine (0.5 or 1 mg/kg) was not enhanced by lower doses of naloxone but was antagonized by higher doses. These data do not support the hypothesis that the naloxone-sensitive anti-analgesic effect of nalbuphine observed in humans is present in the rat and could explain, at least in part, the opposite direction of the sex differences for kappa agonist-antagonist opioid analgesia observed in these two species.

Analgesia↗

PubMed2003

Response of neuropathic trigeminal pain to the combination of low-dose nalbuphine plus naloxone in humans.

We report on the response of medically refractory neuropathic trigeminal pain in three patients to intravenous administration of a combination of the kappa-partial agonist opioid nalbuphine and the opioid antagonist naloxone. Each of the three patients had developed a painful peripheral neuropathy as a complication of chemical or mechanical injury to the trigeminal nerve. Each patient had been tried on a number of analgesics, including mu-opioids, and had not gained relief or was not able to tolerate side effects of the medications. Pain intensity was measured for 3 h following drug administration using a 10 cm visual analog scale. All three patients reported marked decrease in pain following administration of the nalbuphine and naloxone combination. These findings suggest a novel approach to the management for neuropathic pain.

Adult↗

PubMed2003

Sexual dimorphism in very low dose nalbuphine postoperative analgesia.

In recent studies we demonstrated that the analgesic effect of the kappa-like opioids is significantly greater in women, that low dose nalbuphine (5 mg) produces profound anti-analgesia (i.e. enhances pain) in men, and that addition of a low dose of the non-selective opioid receptor antagonist naloxone (0.4 mg) to nalbuphine (5 mg) abolishes the sex difference and results in significantly enhanced analgesia in both sexes. To further delineate the dose-dependent analgesic and anti-analgesic effects of nalbuphine, the present study evaluated the effect of a lower dose of nalbuphine (2.5 mg), with and without naloxone, on dental postoperative pain. In women, nalbuphine alone induced modest, short duration analgesia, which was antagonized rather than enhanced by the addition of naloxone (0.4 mg). In men, this dose of nalbuphine alone did not produce analgesia or anti-analgesia, and naloxone (0.4 mg) did not alter the response to nalbuphine. Thus, the anti-analgesic effect of nalbuphine, present in both sexes at the 5 mg dose disappears at the lower dose of nalbuphine. In addition, the mild analgesia in women produced by this lower dose of nalbuphine is antagonized by naloxone.

Adult↗

PubMed2003

Vagal modulation of spinal nicotine-induced inhibition of the inflammatory response mediated by descending antinociceptive controls.

Noxious stimuli activate neuroendocrine axes, inhibiting inflammation, an effect that is powerfully attenuated by ongoing activity in subdiaphragmatic vagal afferents. To evaluate whether this inhibitory effect of vagal afferent activity is mediated by descending antinociceptive control, we tested whether antagonizing descending antinociceptive controls: (i) enhances the inhibition of inflammation produced by spinal nicotine (which stimulates central terminals of nociceptors) and (ii) occludes the enhancing effect of subdiaphragmatic vagotomy, in the rat. Spinal intrathecal co-administration of the alpha-adrenergic receptor antagonist phentolamine and the non-selective opioid receptor antagonist naloxone, and acute subdiaphragmatic vagotomy each produced enhancement, with similar magnitude, of nicotine-induced inhibition of plasma extravasation, produced by the potent inflammatory mediator, bradykinin. The combination of subdiaphragmatic vagotomy and intrathecal receptor antagonists, however, produced no further enhancement compared to each treatment alone. These findings support the suggestion that activity in descending antinociceptive controls modulates noxious stimulus-induced inhibition of inflammation and the vagal modulation of noxious stimulus-induced inhibition of inflammation is mediated by descending antinociceptive controls.

Adrenergic alpha-Antagonists↗

PubMed2003

Hyperalgesic priming in the rat demonstrates marked sexual dimorphism.

In male rats, carrageenan (CAR)-induced inflammation or exposure to a selective protein kinase C epsilon (PKC epsilon ) agonist (psi epsilon RACK) produces prolongation of the hyperalgesia induced by a subsequent exposure to an inflammatory mediator, a phenomenon referred to as hyperalgesic priming. Since many chronic inflammatory conditions are sexually dimorphic, we tested the hypothesis that hyperalgesic priming is sexually dimorphic. Prior injection of CAR or psi epsilon RACK produced a prolongation of the hyperalgesia induced by a subsequent injection of prostaglandin E(2), from less than 3 h to greater than 24 h, but only in male rats. In ovariectomized female rats priming with CAR and psi epsilon RACK produced hyperalgesic priming effects similar to that observed in the male rat, and this effect was reversed by estrogen replacement. While gonadectomy in males had no effect on CAR and psi epsilon RACK induced hyperalgesic priming, female phenotype was observed following implantation of estrogen in males. Thus, mechanisms mediating the development of hyperalgesic priming produced by inflammation are suppressed by estrogen. This regulation of priming by estrogen appears to occur at or downstream of the activation of PKC epsilon.

Animals↗

PubMed2003

Contribution of spinal glutamatergic mechanisms in heterosegmental antinociception induced by noxious stimulation.

We evaluated the role of spinal glutamate and substance P receptors in noxious stimulus-induced antinociception (NSIA). NSIA was produced by subdermal capsaicin administration in the hind paw of the rat and measured as attenuation of the jaw-opening reflex. NSIA was completely blocked by spinal intrathecal administration of the selective NMDA receptor antagonist LY235959 as well as the mGluR5 antagonists MPEP and SIB-1757 and partially attenuated by the selective AMPA/kainate receptor antagonist NBQX; however, neither the mGluR1 receptor antagonist LY367385 nor the NK1 antagonist L-703,606 affected NSIA. These results suggest that NSIA depends on glutamate, released from the central terminals of the primary afferent nociceptors, acting primarily on NMDA and mGluR5 receptors. Although substance P is also known to be released by similar stimuli, NK1 receptors do not appear to play a role in NSIA. The implications of these findings in the context of a proposed spinal circuit that mediates NSIA are discussed.

Animals↗