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J D Levine

Publications and source records attributed to J D Levine.

At least 37 records · Page 2Linked to original sources
PubMed2001

Endogenous opioids suppress activation of nociceptors by sub-nanomolar nicotine.

1. Nicotine can activate primary afferent nociceptors, one result of which is to increase neurogenic plasma extravasation. In this study we have demonstrated a novel proinflammatory effect of sub-nanomolar nicotine, mediated by peripheral action at sensory neurons. This action is normally masked by adrenal medulla-derived delta-opioid receptor agonists. 2. While neurogenic plasma extravasation in the knee joint of the rat was not increased by intra-articular perfusion of nicotine (10(-8) M), perfusion of nicotine, at concentrations as low as 10(-10) M, combined with naloxone to block opioid receptors (or naltrindole to block delta-opioid receptors) was able to enhance bradykinin-induced plasma extravasation. This pro-inflammatory effect of intra-articular nicotine was mimicked by subcutaneous nicotine which was abolished by intra-articularly-administered hexamethonium, a nicotinic receptor antagonist. 3. Following denervation of the adrenal medulla, intra-articular nicotine, alone at 10(-8) M, enhanced plasma extravasation, which was no longer enhanced by naloxone. 4. Destruction of primary afferents by neonatal treatment with capsaicin or blockade of sensory neurotransmitter by neurokinin-1 receptor antagonist RP-87,580 abolished the pro-inflammatory effect of nicotine. 5. The effect of nicotine we describe in promoting inflammation is exerted at extremely low concentrations and therefore could have relevance to smokers, patients receiving medicinal nicotine as therapy and even second-hand smokers. Since receptor mechanisms on peripheral terminals of nociceptors may also be present on central terminals, actions of the endogenous nicotinic agonist acetylcholine, at central terminals of primary afferents or at other sites in the central nervous system, may be similarly modulated by opioids.

Adrenal Medulla↗
PubMed2001

Sex hormones regulate the contribution of PKCepsilon and PKA signalling in inflammatory pain in the rat.

We have evaluated the contribution of differences in second messenger signalling to sex differences in inflammatory pain and its control by sex hormones. In normal male but not female rats, epinephrine-induced mechanical hyperalgesia was antagonized by inhibitors of protein kinase Cepsilon (PKCepsilon), protein kinase A (PKA) and nitric oxide synthetase (NOS). Similarly, in PKCepsilon knockout mice, a contribution of PKCepsilon to epinephrine-dependent mechanical hyperalgesia occurred in males only. In contrast, hyperalgesia induced by prostaglandin E2, in both females and males, was dependent on PKA and NO. In both sexes, inhibitors of mitogen-activated protein kinase/extracellular-signal related kinase kinase (MEK) inhibited epinephrine hyperalgesia. In gonadectomized females, the second messenger contributions to epinephrine hyperalgesia demonstrated the pattern seen in males. Administration of oestrogen to gonadectomized females fully reconstituted the phenotype of the normal female. These data demonstrate gender differences in PKCepsilon, PKA and NO signalling in epinephrine-induced hyperalgesia which are oestrogen dependent and appear to be exerted at the level of the beta-adrenergic receptor or the G-protein to which it is coupled.

Adrenergic Agonists↗
PubMed2001

Role of adrenal medulla in development of sexual dimorphism in inflammation.

Many inflammatory diseases show a female predilection in adults, but not prepubertally. Because sex differences in the inflammatory response in the adult rat are mediated, in part, by sexual dimorphism in adrenal medullary function, we investigated the contribution of the adrenal medulla to the ontogeny of sexual dimorphism in inflammation. Whilst there was no sex difference in the magnitude of the plasma extravasation (PE) induced by the potent inflammatory mediator bradykinin (BK) in prepubertal rats, in adult rats BK-induced PE was markedly greater in males. Also, adult male rats, gonadectomized prior to puberty, had a lower magnitude of BK-induced PE than did adult male controls, whilst adult females gonadectomized prepubertally had higher BK-induced PE than did controls. In rats gonadectomized after puberty, the magnitude of BK-induced PE in adult males was not affected, whilst in females it resulted in significantly higher BK-induced PE, similar to the effect of prepubertal gonadectomy. When tested prepubertally, adrenal denervation increased the magnitude of BK-induced PE in females, but not in males. In contrast, in both males and females tested as adults, but castrated prepubertally, and in gonad-intact adult females, adrenal denervation significantly increased the magnitude of BK-induced PE. Adrenal denervation in prepubertal females given adult levels of 17beta-oestradiol produced a marked enhancement in the denervation-induced increase in magnitude of BK-induced PE compared to females not exposed prematurely to sex hormones. These studies suggest that an adrenal medulla-dependent inhibition of BK-induced PE is present in female but not male rats, and is enhanced by oestrogen but suppressed by testosterone.

Adrenal Medulla↗
PubMed2001

Gender and gonadal hormone effects on vagal modulation of tonic nociception.

We studied the influence of gender and gonadal hormones on modulation of tonic nociception exerted by vagal activity. In male rats, subdiaphragmatic vagotomy resulted in significantly reduced nociceptive behavior during phase 2 of the formalin test. Whereas gonadectomy alone had no effect, it completely eliminated the suppressive effect of subdiaphragmatic vagotomy; however, sex hormone replacement with either testosterone or dihydrotestosterone did not restore the ability of subdiaphragmatic vagotomy to suppress nociceptive behavior. These results suggest that, in males, a gonad-dependent but androgenic gonadal hormone-independent mechanism contributes to pronociceptive effects of vagal afferent activity. Although neither gonadectomy nor subdiaphragmatic vagotomy alone affected the response to formalin in females, gonadectomy plus vagotomy resulted in significantly reduced nociceptive behavior during phase 2. Reconstitution with 17 beta-estradiol implants in gonadectomized females not only prevented suppression of nociceptive behavior seen with gonadectomy plus vagotomy, but also led to increased nociceptive behavior in the interphase between phases 1 and 2. However, placement of 17 beta-estradiol implants in gonad-intact females had no effect on formalin-induced nociceptive behavior. The finding that estrogen produced an increase in nociceptive behavior in gonadectomized female rats after vagotomy but not in normal female rats (with intact gonads and subdiaphragmatic vagus) suggests that the interaction between estrogen and nociceptive afferent activity is suppressed by vagal function. In conclusion, a nonandrogenic action of testicular function in male rats and estrogen in females seems to influence the effect of vagal activity on formalin-induced nociceptive behavior.

Journal Article↗
PubMed2001

Rapid onset pain induced by intravenous streptozotocin in the rat.

Pain in diabetes is a common debilitating condition for which pathophysiology remains poorly understood. To evaluate the underlying mechanisms, we used intravenous injection of streptozotocin to produce rapid (24-hour) onset of diabetes (blood glucose > 300 mg/dL and urine glucose > 2,000 mg/dL with polyuria). In this model, mechanical and thermal hyperalgesia and tactile allodynia are detectable by 48 hours after streptozotocin administration in the absence of ketonuria or physical debility. Treatment with insulin attenuated hyperglycemia and prevented the development of mechanical and thermal hyperalgesia. Direct application of streptozotocin to peripheral nerve did not produce hyperalgesia. We conclude that streptozotocin can induce pain independent of a general debility or direct toxic effect of streptozotocin on peripheral nerve and that elevated blood glucose may contribute to the enhanced nociception.

Journal Article↗
PubMed2000

Key role for the epsilon isoform of protein kinase C in painful alcoholic neuropathy in the rat.

Chronic alcohol consumption produces a painful peripheral neuropathy for which there is no reliably successful therapy, attributable to, in great part, a lack of understanding of the underlying mechanisms. We tested the hypothesis that neuropathic pain associated with chronic alcohol consumption is a result of abnormal peripheral nociceptor function. In rats maintained on a diet to simulate chronic alcohol consumption in humans, mechanical hyperalgesia was present by the fourth week and maximal at 10 weeks. Thermal hyperalgesia and mechanical allodynia were also present. Mechanical threshold of C-fibers in ethanol fed rats was lowered, and the number of action potentials during sustained stimulation increased. The hyperalgesia was acutely attenuated by intradermal injection of nonselective protein kinase C (PKC) or selective PKCepsilon inhibitors injected at the site of nociceptive testing. Western immunoblot analysis indicated a higher level of PKCepsilon in dorsal root ganglia from alcohol-fed rats, supporting a role for enhanced PKCepsilon second-messenger signaling in nociceptors contributing to alcohol-induced hyperalgesia.

Action Potentials↗
PubMed2000

Nociceptive neuroendocrine negative feedback control of neurogenic inflammation activated by capsaicin in the rat paw: role of the adrenal medulla.

Recently we have found that inhibition of bradykinin-induced synovial plasma extravasation by transcutaneous electrical stimulation at strengths which excite unmyelinated afferent axons is mediated by the hypothalamo-pituitary-adrenal axis. Here we tested whether stimulation of nociceptors in the rat paw by intradermally injected capsaicin inhibits bradykinin-induced synovial plasma extravasation and whether this inhibition is mediated by the hypothalamo-pituitary-adrenal or sympatho-adrenal axis. Furthermore, we tested whether inhibition of bradykinin-induced plasma extravasation generated by intraperitoneally injected capsaicin, which preferentially excites visceral afferents, is mediated by the hypothalamo-pituitary-adrenal or sympatho-adrenal axis. We used normal rats, subdiaphragmatically vagotomized rats, rats with denervated adrenal medullae and rats with acutely transected spinal cords at the segmental levels T1/T2 or T12/L1. Injection of capsaicin into the plantar or palmar surface of the paws produced a depression of bradykinin-induced plasma extravasation. The inhibition elicited from the forepaw was larger than that from the hindpaw. The inhibition of bradykinin-induced plasma extravasation elicited from both paws was potentiated by subdiaphragmatic vagotomy. Denervation of the adrenal medullae abolished the inhibitory effect of intradermal capsaicin in vagus-intact and in vagotomized animals. After spinalization at the segmental level T1/T2, capsaicin injected into the forepaw did not depress bradykinin-induced plasma extravasation either in vagus-intact or in vagotomized animals. Capsaicin injected into the hindpaw in these spinalized animals produced a small depression. After spinalization at the segmental level T12/L1 no depression was produced by capsaicin injected into the hindpaw. Depression of bradykinin-induced plasma extravasation generated by intraperitoneal injection of capsaicin in vagus-intact and in vagotomized animals was also abolished or attenuated after denervation of the adrenal medullae. This shows that this depression was also largely dependent on the activation of the sympatho-adrenal system. We conclude that depression of bradykinin-induced plasma extravasation during stimulation of nociceptors by capsaicin is mediated predominantly by the sympathoadrenal pathway. This finding differs from the inhibitory mechanism of depression of bradykinin-induced plasma extravasation generated by cutaneous electrical stimulation, which is mediated by the hypothalamo-pituitary-adrenal axis.

Adrenal Medulla↗
PubMed2000

Damage to the cytoskeleton of large diameter sensory neurons and myelinated axons in vincristine-induced painful peripheral neuropathy in the rat.

Vincristine, along with other antimitotic chemotherapeutic drugs, produces a peripheral neuropathy in humans that is accompanied by painful paresthesias, dysesthesias, and occasionally hypoesthesia, and by hyporeflexia (Holland et al. [1973] Cancer Res. 33:1258-1264; McLeod and Penny [1969] J Neurol Neurosurg Psychiatry 32:297-304; Postma et al. [1993] J Neurooncol. 15:23-27; Sandler et al. [1969] Neurology 19:367-374). Systemic administration of vincristine causes swelling of unmyelinated axons and disorientation of axonal microtubules (Tanner et al. [1998a1998a] J Comp Neurol. 395:481-492) at a time when it also produces allodynia and mechanical hyperalgesia (Aley et al. [1996] Neuroscience 73:259-265; Authier et al. [1999] Neuroreport 10:965-968) and enhanced responsiveness in C-fibers in the rat (Tanner et al. [1998b] J Neurosci. 18:6480-6491). Because slowing of A-fiber conduction velocities had also been demonstrated (Tanner et al. [1998b] J Neurosci. 18:6480-6491), and mechanical hyperalgesia can occur secondary to damage to large diameter sensory afferents (Basbaum et al. [1991] Can J Physiol Pharmacol. 69:647-651; Coggeshall et al. [1993] Pain 52:233-242; Woolf and Mannion [1999] Lancet 353:1959-1964), we sought to determine whether vincristine also induced ultrastructural changes in myelinated A-fibers. Moreover, since systemic treatment with vincristine did not cause profound microtubule depolymerization in the unmyelinated axons of the peripheral nerve, we hypothesized that the drug's effects may be more extensive in the cell body, because in the spinal ganglion, the blood-nerve barrier is less restrictive. We used quantitative ultrastructural methods to analyze the microtubule cytoskeleton in myelinated axons in the mid-shaft of the saphenous nerve and in the sensory ganglion cells. Vincristine induced swelling of the whole nerve and an increase in the cross-sectional areas of myelinated axons but no loss of myelinated axons. There was a significant decrease in axonal microtubules, as well as microtubule disorganization, in myelinated fibers from vincristine-treated rats. In the spinal ganglion, vincristine induced swelling of large diameter sensory neurons and a build-up of neurofilaments in the cell bodies and proximal axons, suggestive of impaired anterograde axonal transport.

Animals↗
PubMed2000

The stretch-inactivated channel, a vanilloid receptor variant, is expressed in small-diameter sensory neurons in the rat.

Exposure to hypertonic conditions is known to produce pain and activate small-diameter sensory neurons. Recently, the vanilloid receptor variant and stretch-inactivated ion channel (SIC) was cloned and shown to mediate an inward current in response to cell shrinkage. Since other vanilloid receptors have been previously shown to mediate nociception, we investigated whether SIC is expressed in sensory neurons. Using reverse transcription-polymerase chain reaction and in situ hybridization techniques, we identified SIC in the neurons of dorsal root and trigeminal ganglia. Furthermore, SIC was found to be present almost exclusively in the small-diameter sensory neurons, which includes the nociceptive population. Since SIC is activated by cell shrinkage, it may participate in the mediation of pain produced by hypertonic stimuli.

Amino Acid Sequence↗
PubMed2000

Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C.

We have identified a mechanism, mediated by the epsilon isozyme of protein kinase C (PKCepsilon) in peripheral neurons, which may have a role in chronic inflammatory pain. Acute inflammation, produced by carrageenan injection in the rat hindpaw, produced mechanical hyperalgesia that resolved by 72 hr. However, for up to 3 weeks after carrageenan, injection of the inflammatory mediators prostaglandin E(2) or 5-hydroxytryptamine or of an adenosine A(2) agonist into the same site induced a markedly prolonged hyperalgesia (>24 hr compared with 5 hr or less in control rats not pretreated with carrageenan). A nonselective inhibitor of several PKC isozymes and a selective PKCepsilon inhibitor antagonized this prolonged hyperalgesic response equally. Acute carrageenan hyperalgesia could be inhibited by PKA or PKG antagonists. However, these antagonists did not inhibit development of the hypersensitivity to inflammatory mediators. Our findings indicate that different second messenger pathways underlie acute and prolonged inflammatory pain.

Adenosine↗
PubMed2000

Molecular cloning of an N-terminal splice variant of the capsaicin receptor. Loss of N-terminal domain suggests functional divergence among capsaicin receptor subtypes.

Recently a cDNA clone, vanilloid receptor subtype-1 (VR1), was isolated and found to encode an ion channel that is activated by both capsaicin, the pain producing compound in chili peppers, and by noxious thermal stimuli. Subsequently, two related cDNAs have been isolated, a stretch inactivating channel with mechanosensitive properties and a vanilloid receptor-like protein that is responsive to high temperatures (52-53 degrees C). Here, we report the isolation of a vanilloid receptor 5'-splice variant (VR.5'sv) which differs from VR1 by elimination of the majority of the intracellular N-terminal domain and ankyrin repeat elements. Both VR.5'sv and VR1 mRNA were shown to be expressed in tissues reportedly responsive to capsaicin including dorsal root ganglion, brain, and peripheral blood mononuclear cells. Functional expression of VR.5'sv in Xenopus oocytes and mammalian cells showed no sensitivity to capsaicin, the potent vanilloid resiniferatoxin, hydrogen ions (pH 6.2), or noxious thermal stimuli (50 degrees C). Since VR.5'sv is otherwise identical to VR1 throughout its transmembrane spanning domains and C-terminal region, these results support the hypothesis that the N-terminal intracellular domain is essential for the formation of functional receptors activated by vanilloid compounds and noxious thermal stimuli.

Amino Acid Sequence↗
PubMed2000

The role of vagal visceral afferents in the control of nociception.

We have shown that activity in subdiaphragmatic vagal afferents modulates mechanical hyperalgesic behavior in the rat. Subdiaphragmatic vagotomy decreases paw-withdrawal threshold to mechanical stimulation (baseline and after intradermal injection of bradykinin), thus enhancing mechanical hyperalgesic behavior. Most of this decrease is generated by an endocrine signal released by the adrenal medullae because denervation or removal of the adrenal medullae prevents or reverses these changes. This novel mechanism may imply that: (a) the brain is able to regulate sensitivity of nociceptors all over the body by a neuroendocrine mechanisms, (b) sensitivity of nociceptors can be influenced by changes in parts of the body which are remote from the location of the sensitized nociceptors and (c) circulating catecholamines can influence nociceptors in a way which is different from those reported so far (see Jänig and McLachlan, 1994; Jänig, 1996a; Jänig et al., 1996).

Animals↗
PubMed2000

Trigeminal neuralgia: opportunities for research and treatment.

Trigeminal neuralgia was the focus of a recent workshop convened by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Dental and Craniofacial Research (NIDCR). The workshop brought together basic scientists, clinicians, epidemiologists, and patient advocates. New research directions for epidemiology, diagnosis and assessment, pain mechanisms, and treatment were identified. (The workshop was held in Rockville MD on September 14, 1999, with financial support from NINDS, NIDCR, the NIH Office of Rare Diseases, and the NIH Pain Research Consortium.)

Animals↗
PubMed1999

Bradykinin-induced neurogenic migration of neutrophils into the rat knee joint.

This study examined the dependence of neurogenic and non-neurogenic synovial plasma extravasation on neutrophils. Perfusion of bradykinin into the knee joint produced both a rapid increase in the magnitude of plasma extravasation and a significant increase in number of neutrophils in the synovium. Both bradykinin-induced plasma extravasation and neutrophil accumulation were dependent on sympathetic post-ganglionic neuron terminals, since both were blocked in sympathectomized rats. Platelet activating factor, which produces plasma extravasation independent of sympathetic neurons, did not increase the number of neutrophils in the synovium. These findings support the suggestion that bradykinin acts on sympathetic nerve terminals in the knee leading to attraction of neutrophils, which promotes plasma extravasation.

Animals↗
PubMed1999

Repeated, but not acute, stress suppresses inflammatory plasma extravasation.

Clinical findings suggest that inflammatory disease symptoms are aggravated by ongoing, repeated stress, but not by acute stress. We hypothesized that, compared with single acute stressors, chronic repeated stress may engage different physiological mechanisms that exert qualitatively different effects on the inflammatory response. Because inhibition of plasma extravasation, a critical component of the inflammatory response, has been associated with increased disease severity in experimental arthritis, we tested for a potential repeated stress-induced inhibition of plasma extravasation. Repeated, but not single, exposures to restraint stress produced a profound inhibition of bradykinin-induced synovial plasma extravasation in the rat. Experiments examining the mechanism of inhibition showed that the effect of repeated stress was blocked by adrenalectomy, but not by adrenal medullae denervation, suggesting that the adrenal cortex mediates this effect. Consistent with known effects of stress and with mediation by the adrenal cortex, restraint stress evoked repeated transient elevations of plasma corticosterone levels. This elevated corticosterone was necessary and sufficient to produce inhibition of plasma extravasation because the stress-induced inhibition was blocked by preventing corticosterone synthesis and, conversely, induction of repeated transient elevations in plasma corticosterone levels mimicked the effects of repeated stress. These data suggest that repetition of a mild stressor can induce changes in the physiological state of the animal that enable a previously innocuous stressor to inhibit the inflammatory response. These findings provide a potential explanation for the clinical association between repeated stress and aggravation of inflammatory disease symptoms and provide a model for study of the biological mechanisms underlying the stress-induced aggravation of chronic inflammatory diseases.

Adrenocorticotropic Hormone↗
PubMed1999

Mechanical transduction by rat dorsal root ganglion neurons in vitro.

Although it is generally presumed that mechanical sensitivity of somatosensory nerve fibers results from the activation of mechanosensitive ion channels, a mechanically-gated whole-cell current has never been demonstrated in dorsal root ganglion (DRG) neurons. We performed patch clamp experiments on rat DRG neurons in culture, and report the first mechanically-activated current in somatosensory neurons (I(mech)). This whole-cell current is observed in most dorsal root ganglion neurons but not in non-sensory sympathetic ganglion neurons. The current-voltage relation of I(mech) indicates that it is a non-selective cation current. Sensitivity of I(mech) to block by gadolinium suggests that it may be mediated by a member of a family of mechanosensitive non-selective cation channels observed in many cell types. Sensitivity to benzamil supports this idea, and further suggests that the current might be mediated by a member of the degenerin/ epithelial sodium channel (DEG/ENaC) family.

Action Potentials↗
PubMed1999

Pain-induced analgesia mediated by mesolimbic reward circuits.

We tested the hypothesis that noxious stimuli induce pain modulation by activation of supraspinal structures. We found that intense noxious stimuli (i.e., subdermal injection of capsaicin or paw immersion in hot water) induced profound attenuation of the jaw-opening reflex in the anesthetized rat; forepaw subdermal capsaicin also elevated the mechanical hindpaw-withdrawal threshold in the awake rat. These antinociceptive effects were blocked by previous injection of either a dopamine antagonist (flupentixol) or an opioid antagonist (naloxone) into the nucleus accumbens. Additional experiments in anesthetized animals showed that the antinociceptive effect of noxious stimulation by either capsaicin (>/=100 micrograms) or hindpaw immersion in hot water (>/=45 degrees C for 4 min) correlated with the intensity of the stimulus. The maximal antinociceptive effect of capsaicin was similar in magnitude to that of a high dose of morphine (10 mg/kg) injected subcutaneously. Injection of the GABA(A)-receptor agonist muscimol, but not naloxone, into the rostroventral medulla, a major component of descending pain modulation systems, blocked capsaicin-induced antinociception. Although it is widely thought that painful stimuli may induce analgesia by activating forebrain structures, this is the first demonstration that such a mechanism exists. Furthermore, this mechanism can be engaged by naturalistic stimuli in awake animals. These observations imply that painful stimuli might under certain conditions be rewarding.

Analgesia↗