ReN-1869 [(R)-1-(3-(10,11-Dihydro-5 H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidine Carboxylic Acid], a Novel Histamine H1 Receptor Antagonist, Produces Potent and Selective Antinociceptive Effects on Dorsal Horn Neurons after Inflammation and Neuropathy

Suzuki, Rie; Edwards, Mark J.; Dickenson, Anthony H.

doi:10.1124/jpet.103.063511

Cited by 4 publications

(1 citation statement)

References 37 publications

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“…One hour stimulation of mast cells with TNP is sufficient to induce degranulation, release of histamine and other preformed mediators [26]. Intrathecal histamine administration is pro-nociceptive in mice [27] and spinal histamine receptor antagonists show anti-nociceptive efficacy in various animal models [28]. Given the heterogeneity of mast cells between tissues responsible for their phenotype [1,29] and even within the dura [17], we believe that using mouse bone-marrow cultured mast cells which are less homogeneous than their rat equivalents [30] is still appropriate here.…”

Section: Discussionmentioning

confidence: 99%

Central Nervous System Mast Cells in Peripheral Inflammatory Nociception

et al. 2011

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BackgroundFunctional aspects of mast cell-neuronal interactions remain poorly understood. Mast cell activation and degranulation can result in the release of powerful pro-inflammatory mediators such as histamine and cytokines. Cerebral dural mast cells have been proposed to modulate meningeal nociceptor activity and be involved in migraine pathophysiology. Little is known about the functional role of spinal cord dural mast cells. In this study, we examine their potential involvement in nociception and synaptic plasticity in superficial spinal dorsal horn. Changes of lower spinal cord dura mast cells and their contribution to hyperalgesia are examined in animal models of peripheral neurogenic and non-neurogenic inflammation.ResultsSpinal application of supernatant from activated cultured mast cells induces significant mechanical hyperalgesia and long-term potentiation (LTP) at spinal synapses of C-fibers. Lumbar, thoracic and thalamic preparations are then examined for mast cell number and degranulation status after intraplantar capsaicin and carrageenan. Intradermal capsaicin induces a significant percent increase of lumbar dural mast cells at 3 hours post-administration. Peripheral carrageenan in female rats significantly increases mast cell density in the lumbar dura, but not in thoracic dura or thalamus. Intrathecal administration of the mast cell stabilizer sodium cromoglycate or the spleen tyrosine kinase (Syk) inhibitor BAY-613606 reduce the increased percent degranulation and degranulated cell density of lumbar dural mast cells after capsaicin and carrageenan respectively, without affecting hyperalgesia.ConclusionThe results suggest that lumbar dural mast cells may be sufficient but are not necessary for capsaicin or carrageenan-induced hyperalgesia.

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Section: Discussionmentioning

confidence: 99%

Central Nervous System Mast Cells in Peripheral Inflammatory Nociception

et al. 2011

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Differential pharmacological modulation of the spontaneous stimulus-independent activity in the rat spinal cord following peripheral nerve injury

Suzuki

Dickenson

2006

Experimental Neurology

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NK-1 receptors in the rostral ventromedial medulla contribute to hyperalgesia produced by intraplantar injection of capsaicin

Pacharinsak

Khasabov

Beitz

et al. 2008

Pain

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The rostral ventromedial medulla (RVM) is an area of the brainstem involved in the descending modulation of nociception at the level of the spinal cord. Although the RVM is involved in the inhibition or facilitation of nociception, the underlying mechanisms are not understood. Here we examined the role of the neuropeptide substance P and neurokinin-1 (NK-1) receptors located in the RVM on withdrawal responses evoked by mechanical and heat stimuli applied to the rat hindpaw under normal conditions and during hyperalgesia produced by capsaicin. The mechanical withdrawal threshold was obtained using von Frey monofilaments applied to the plantar surface of the hindpaw. Sensitivity to heat was determined by measuring the latency to withdrawal from radiant heat applied to the plantar surface. Mechanical and heat hyperalgesia were defined as a decrease in withdrawal response threshold or latency, respectively. Rats were prepared with a chronic cannula and either vehicle or the NK-1 receptor antagonists, L-733,060 or RP-67580, was injected into the RVM. Paw withdrawal responses were obtained before and after RVM injection, and then at 5, 30, and 60 min after an intraplantar injection of capsaicin (10 microg). Injection of the NK-1 antagonists at doses of 0.5 pmol or higher did not alter withdrawal responses to mechanical or heat stimuli under normal conditions but reduced the duration of nocifensive behavior and the mechanical and heat hyperalgesia produced by capsaicin. These findings suggest that the activation of NK-1 receptors in the RVM contributes to the hyperalgesia produced by capsaicin.

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ReN-1869 [(R)-1-(3-(10,11-Dihydro-5 H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidine Carboxylic Acid], a Novel Histamine H1 Receptor Antagonist, Produces Potent and Selective Antinociceptive Effects on Dorsal Horn Neurons after Inflammation and Neuropathy

Cited by 4 publications

References 37 publications

Central Nervous System Mast Cells in Peripheral Inflammatory Nociception

Central Nervous System Mast Cells in Peripheral Inflammatory Nociception

Differential pharmacological modulation of the spontaneous stimulus-independent activity in the rat spinal cord following peripheral nerve injury

NK-1 receptors in the rostral ventromedial medulla contribute to hyperalgesia produced by intraplantar injection of capsaicin

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