Search

Aims: Investigate the involvement of the histaminergic projections from tuberomammillary nucleus (TMN) to the spinal cord in the modulation of nociception and peripheral edema in a model of monoarthritis., Main Methods: Subacute monoarthritis was induced by an intraarticular injection of carrageenan followed by LPS 72 h later. Disability and joint edema were assessed at the 3rd hour after LPS and at every hour up to 6 h., Key Findings: Intrathecal administration of histamine potentiated joint incapacitation and edema, while the H1R antagonist cetirizine decreased both. The H3R agonist immepip decreased both incapacitation and edema, while the H3R antagonist thioperamide had the opposite effect. The microinjection of glutamate into the ventral TMN (vTMN) caused an increase of incapacitation and articular edema, whereas the blockade of this nucleus by cobalt chloride inhibited both parameters. Intrathecal administration of cetirizine prevented the increase of incapacitation and joint edema caused by glutamate microinjection into the vTMN. Similarly, an intrathecal injection of the NKCC1 cotransporter inhibitor bumetanide prevented the effects of glutamate microinjection into the vTMN, whereas coadministration of histamine with bumetanide only inhibited the potentiation of joint edema. A microinjection of orexin B into the vTMN potentiated incapacitation and joint edema, while coadministration of the OX1/2 receptor antagonist almorexant with orexin B did not., Significance: These data support the notion that TMN participates in the modulation of a peripheral inflammatory process by means of histaminergic projections to the spinal cord, and the hypothalamus may trigger TMN activation by means of glutamate and orexin., (Copyright © 2020. Published by Elsevier Inc.)

Background: Histamine receptors are known to participate in spinal cord nociceptive transmission, and previous studies have suggested that histaminergic receptors are involved in the analgesic effects of morphine. Herein, we investigated the effect of intrathecal injection of histaminergic agonists and antagonists in a model of acute articular inflammation and their interaction with morphine., Methods: After carrageenan injection in the right knee joint, articular incapacitation was measured hourly, for up to 6 hours, by the paw elevation time during 1-minute periods of stimulated walking. Inflammatory edema was also assessed hourly by determining an increase in articular diameter. Spinal treatments were administered 20 minutes before knee-joint carrageenan injection and were compared with the saline-treated control group., Results: Intrathecally injected histamine increased incapacitation and articular edema, whereas the H1R antagonist, cetirizine, decreased both parameters. The H3R agonist, immepip, decreased both incapacitation and edema, but the H3R antagonist, thioperamide, increased both incapacitation and edema. Morphine inhibited both incapacitation and edema. Furthermore, combining a subeffective dose of morphine with cetirizine or immepip potentiated the analgesic and antiedematogenic effect., Conclusions: Histamine seems to act at the spinal level via H1 and H3 receptors to modulate acute arthritis in rats. An H1R antagonist and H3R agonist were found to potentiate the analgesic and antiedematogenic effects of morphine, suggesting that histaminergic and opioid spinal systems may be explored for means of improving analgesia, as well as peripheral anti-inflammatory effects.

It is known that primary afferent central terminal sensitization can influence peripheral inflammation, however, it remains to be understood whether spinal cord glia can also contribute to this process. Our aim was to investigate the effect of spinal cord glia inhibition on the pathogenesis of LPS-induced knee-joint monoarthritis in rats and also to investigate the role of fractalkine and TNF-α. LPS was injected into the knee-joint previously primed with carrageenan to cause articular incapacitation, edema, synovial leukocyte infiltration, and GFAP and CD11b/c spinal immunoreactivity (glia-IR) increase. Articular edema was more sensitive to the inhibition by intrathecal fluorocitrate and minocycline than nociception and synovial leukocyte content. The higher doses of both drugs were ineffective when given by intraperitoneal route. Corticosteroid synthesis inhibition by aminoglutethimide did not change the glia inhibitors effect. The inhibitory effect of the dorsal root potential inhibitor, furosemide, was not additive to that caused by fluorocitrate and minocycline. Intrathecal anti-fractalkine and anti-TNF-α inhibited edema, nociception, and synovial leukocytes, while fractalkine caused the opposite effects. The fractalkine effect was inhibited by fluorocitrate and anti-TNF-α. Finally, fluorocitrate, minocycline and anti-fractalkine attenuated, but fractalkine increased, GFAP and CD11b/c IR. The evidence reported herein supports the hypothesis that spinal fractalkine release is involved in glia activation, which via the spinal release of TNF-α, seems to be involved in the development and maintenance of this arthritis model. A possible modulation of the dorsal root reflexes is discussed. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Morphine can inhibit inflammatory edema in experimental animals. The mechanisms and sites by which opioids exert this effect are still under debate. Since the spinal level is a site for modulation of the neurogenic component of inflammation, we investigated the effect of intrathecal (i.t.) administration of morphine, and the involvement of spinal nitric oxide (NO)/cyclic-guanosine monophosphate-GMP pathway in carrageenan (CG)-induced paw edema., Methods: Male Wistar rats received i.t. injections of drugs (20 microL) 30 min before paw stimulation with CG (150 microg). Edema was measured as paw volume increase (mL), and neutrophil migration was evaluated indirectly by myeloperoxidase (MPO) assay., Results: Morphine (37, 75, and 150 nmol) inhibited inflammatory edema, but had no effect on MPO activity. Coinjection with naloxone (64 nmol) reversed the effect of morphine. The corticosteroid synthesis inhibitor, aminoglutethimide (50 mg/kg, v.o.), administered 90 min before morphine injection did not modify its antiedematogenic effect. Low doses of the NO synthase inhibitor, N(omega)-nitro-L-arginine (L-NNA; 10 and 30 pmol) increased, while higher doses (3 and 30 nmol) inhibited edema. The guanylate cyclase inhibitor 1H-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 21 and 42 nmol) increased, while the phosphodiesterase type 5 inhibitor sildenafil (0.15 and 1.5 nmol) inhibited paw edema. Coadministration of a subeffective dose of L-NNA (3 pmol) or ODQ (10 nmol) with morphine prevented its antiedematogenic effect, but sildenafil (0.15 nmol) rendered a subeffective dose of morphine effective (18 nmol). ODQ also prevented the antiedematogenic effect of the NO donor S-nitroso-N-acetyl-penicilamine., Conclusion: These results support the idea that morphine can act on opioid receptors at the spinal level to produce antiedematogenic, and that the NO/cGMP pathway seems to be an important mediator in this effect.

We investigated the effect of serotonergic agonists and antagonists injected intrathecally by direct punction of the spinal cord at the lumbar level (between L5-L6) on peripheral inflammatory edema. Edema was induced by carrageenan injected subcutaneously in one hindpaw 30 min after spinal treatments. Serotonin (0.1, 1, 10 pmol) caused a graded-inhibition of the inflammatory paw edema. The corticosteroid inhibitor aminoglutethimide (100 mg/kg, p.o. 1.5 h before spinal treatment) did not modify this effect. The 5-HT1A agonist buspirone and the 5-HT1B/1D agonist sumatriptan (0.1, 1.0 and 10 nmol) also inhibited paw edema. The 5-HT1,2 antagonist methysergide (10 and 100 pmol) enhanced edema, but higher doses ( 4 and 8 nmol) diminished edema. NAN-190 (5-HT1 antagonist; 1 and 10 nmol) increased paw edema, while ritanserin (5-HT2 antagonist; 1 nmol) inhibited paw edema. Ondansetron (5-HT3 antagonist; up to 10 nmol) did not affect edema, but metoclopramide (5-HT3 antagonist / 5-HT4 agonist; 5, 10 and 30 pmol) inhibited edema. These data suggest that a tonic release of serotonin in the spinal cord may occurs during ongoing peripheral inflammation, modulating the neurogenic component of edema either by an inhibitory action on 5-HT1 receptors or by a stimulatory action on 5-HT2 receptors. A disfunction in such mechanism may be involved in the pathophysiology of certain types of headaches or migraine, which seem to depend on neurogenic vasodilation, and may also help to explain the therapeuthic effectiveness of some serotonergic agents in these conditions.

In the present study, we evaluated the consequences of prostaglandin E(2) (PGE(2)) or indomethacin injection into the spinal cord, on a model of peripheral inflammatory edema. Male Wistar rats (200-250 g) received PGE(2) (10 and 100 ng), intrathecally, at 2, 15, 30, and 60 min before an intraplantar carrageenan (CG; 300 microg) injection into the right hindpaw. The developing edema was measured hourly after CG injection, and the groups injected with PGE(2) 30 and 60 min before CG, presented significant edema potentiation. On the other hand, indomethacin (0.3, 0.6, 1.2, 2.5, and 5.0 microg) given intrathecally 60 min before CG injection, inhibited edema formation dose-dependently. The indomethacin effect was not inhibited by aminoglutethimide, which suggests that it was independent of endogenous steroid production. In addition, intrathecally given PGE(2) (10 and 100 ng) dose-dependently reversed the anti-edematogenic effect of indomethacin given by the same route (2.5 microg, i.t.). This suggests that the anti-edematogenic effect produced by intrathecally given indomethacin is probably due to prostaglandin synthesis inhibition at the spinal cord. It is suggested here that during inflammation, prostaglandin may be released into the spinal cord potentiating dorsal root reflexes that contribute to the peripheral edema formation. The inhibition of this potentiation by indomethacin may be a mechanism embedded into the overall anti-inflammatory action of this drug.