Hemokinin-1 is an important mediator of pain in mouse models of neuropathic and inflammatory mechanisms

Hunyady, Ágnes; Hajna, Zsófia; Gubányi, Tímea; Scheich, Bálint; Kemény, Ágnes; Gaszner, Balázs; Borbély, Éva; Helyes, Zsuzsanna

doi:10.1016/j.brainresbull.2019.01.015

Cited by 15 publications

(21 citation statements)

References 47 publications

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“…Previous studies by our and other groups have established that HK-1 contributes to the development of hyperalgesia in both acute and chronic pain models. HK-1 can elicit pain when injected intrathecally [34,43], and Tac4 -/mice have reduced nocifensive behavior in chemically-induced pain and suppressed hyperalgesia/allodynia in chronic inflammatory and neuropathic pain models [41,102]. In inflammatory pain and arthritis, a pro-inflammatory component is also likely to contribute to its action, since HK-1 expression was described in the immune system as well [30,33,103] and Tac4 deficiency also alleviated experimental lung inflammation [42].…”

Section: Discussionmentioning

confidence: 99%

“…In inflammatory pain and arthritis, a pro-inflammatory component is also likely to contribute to its action, since HK-1 expression was described in the immune system as well [30,33,103] and Tac4 deficiency also alleviated experimental lung inflammation [42]. On the other hand, HK-1 was shown to have a direct role in central nociceptive sensitization, as spinal microglia and astrocyte activation was also attenuated in Tac4 -/mice after nerve injury [41]. HK-1 is a potent NK-1 receptor agonist [34], and most of its effects can be explained by NK-1 receptor activation.…”

Section: Discussionmentioning

confidence: 99%

“…Although a few studies reported antibody development (e.g., [38]) or a recent immunohistochemical study on the TG with an in-house developed antibody [39], there are still no commercially available antibodies against HK-1. Despite the structural similarities and common receptors of HK-1 and SP, some of their functions appear to be different, even opposing each other [36,[40][41][42][43]. This could be explained by different binding sites and different signalling pathways by HK-1 compared to SP even at the NK-1 receptor, but a specific target is suggested to mediate several actions of HK-1 [36].…”

Section: Introductionmentioning

confidence: 98%

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Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization

Aczél

Kecskés

Kun

et al. 2020

IJMS

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A large percentage of primary sensory neurons in the trigeminal ganglia (TG) contain neuropeptides such as tachykinins or calcitonin gene-related peptide. Neuropeptides released from the central terminals of primary afferents sensitize the secondary nociceptive neurons in the trigeminal nucleus caudalis (TNC), but also activate glial cells contributing to neuroinflammation and consequent sensitization in chronic orofacial pain and migraine. In the present study, we investigated the newest member of the tachykinin family, hemokinin-1 (HK-1) encoded by the Tac4 gene in the trigeminal system. HK-1 had been shown to participate in inflammation and hyperalgesia in various models, but its role has not been investigated in orofacial pain or headache. In the complete Freund’s adjuvant (CFA)-induced inflammatory orofacial pain model, we showed that Tac4 expression increased in the TG in response to inflammation. Duration-dependent Tac4 upregulation was associated with the extent of the facial allodynia. Tac4 was detected in both TG neurons and satellite glial cells (SGC) by the ultrasensitive RNAscope in situ hybridization. We also compared gene expression changes of selected neuronal and glial sensitization and neuroinflammation markers between wild-type and Tac4-deficient (Tac4-/-) mice. Expression of the SGC/astrocyte marker in the TG and TNC was significantly lower in intact and saline/CFA-treated Tac4-/- mice. The procedural stress-related increase of the SGC/astrocyte marker was also strongly attenuated in Tac4-/- mice. Analysis of TG samples with a mouse neuroinflammation panel of 770 genes revealed that regulation of microglia and cytotoxic cell-related genes were significantly different in saline-treated Tac4-/- mice compared to their wild-types. It is concluded that HK-1 may participate in neuron-glia interactions both under physiological and inflammatory conditions and mediate pain in the trigeminal system.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization

Aczél

Kecskés

Kun

et al. 2020

IJMS

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“…Traumatic mononeuropathy was achieved by one-third to one-half part ligation of the right sciatic nerve [55]. Significant decrease in the mechanical threshold develops 7 days after operation [56,69,70]. The mechanonociceptive threshold of the plantar surface of the hindpaws was measured by DPA on the 7th postoperative day.…”

Section: Chronic Traumatic Neuropathic Pain Modelmentioning

confidence: 99%

Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain

Kántás

Börzsei

Szöke

et al. 2019

IJMS

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Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst 4 receptor without endocrine actions. Therefore, sst 4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst 4 -linked G-protein activation on stable receptor expressing cells (1 nM to 10 µM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1-C4) bind to the same binding site of the sst 4 receptor with similar interaction energy to high-affinity reference sst 4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC 50 : 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst 4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives. strongly limited by its diverse effects and rapid degradation and consequently short elimination half-life (<3 min) [9]. However, stable and potent synthetic analogs could be potential analgesic candidates.A wide range of somatostatin effects are mediated via five inhibitory G-protein-coupled receptor subtypes (GPCRs) [10,11] which have seven transmembrane domains (TMDs). They are divided into two classes on the basis of their phylogeny, structural homologies and pharmacological properties. The somatotropin release-inhibiting factor 1 (SRIF1) receptor class involves sst 2 , sst 3 and sst 5 mediating important endocrine actions of somatostatin (e.g., inhibition of growth hormone, insulin, glucagon secretion), and the SRIF2 class includes sst 1 and sst 4 [10]. It is well known that sst 4 receptor is present in the dorsal root ganglia cells and spinal cord dorsal horn, and can also mediate analgesic effects along with the δ-opioid receptor [12,13]. We provided several lines of evidence that the broad anti-inflammatory, antinociceptive and anti-hyperalgesic effects of somatostatin are mediated by the sst 4 receptor without influencing endocrine functions [1,4,[14][15][16][17]. Therefore, the sst 4 receptor has become a well-established novel drug target and the development of sst 4 agonists has recently been included in the scope of several pharmaceutical companies [13,[18][19][20][21][22][23].Several hepta-and octapeptide somatostatin analogs, such as 25], were shown to induce anti-inflammatory and antinociceptive effects [13,[26][27][28][29], predominantly via sst 4 activ...

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“…Our research group was the first to describe the mediator role of HK-1 in the chronic adjuvant-induced mouse model of inflammation and related nociception (Borbély et al, 2013). Recently, we proved that HK-1 is involved not only in inflammatory, but also nerve ligation-induced neuropathic pain, which develops independently of inflammation with prominent central sensitization mechanisms (Hunyady et al, 2019). The present work focused on investigating the involvement of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain, nociceptive sensory neurons and the molecular mechanism of action.…”

Section: Introductionmentioning

confidence: 98%

Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons

et al. 2021

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The tachykinin hemokinin-1 (HK-1) is involved in immune cell development and inflammation, but little is known about its function in pain. It acts through the NK1 tachykinin receptor, but several effects are mediated by a yet unidentified target. Therefore, we investigated the role and mechanism of action of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain. Arthritis was induced by i.p. K/BxN serum (passive transfer of inflammatory cytokines, autoantibodies), intra-articular mast cell tryptase or Complete Freund’s Adjuvant (CFA, active immunization) in wild type, HK-1- and NK1-deficient mice. Mechanical- and heat hyperalgesia determined by dynamic plantar esthesiometry and increasing temperature hot plate, respectively, swelling measured by plethysmometry or micrometry were significantly reduced in HK-1-deleted, but not NK1-deficient mice in all models. K/BxN serum-induced histopathological changes (day 14) were also decreased, but early myeloperoxidase activity detected by luminescent in vivo imaging increased in HK-1-deleted mice similarly to the CFA model. However, vasodilation and plasma protein extravasation determined by laser Speckle and fluorescent imaging, respectively, were not altered by HK-1 deficiency in any models. HK-1 induced Ca2+-influx in primary sensory neurons, which was also seen in NK1-deficient cells and after pertussis toxin-pretreatment, but not in extracellular Ca2+-free medium. These are the first results showing that HK-1 mediates arthritic pain and cellular, but not vascular inflammatory mechanisms, independently of NK1 activation. HK-1 activates primary sensory neurons presumably via Ca2+ channel-linked receptor. Identifying its target opens new directions to understand joint pain leading to novel therapeutic opportunities.

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Hemokinin-1 is an important mediator of pain in mouse models of neuropathic and inflammatory mechanisms

Cited by 15 publications

References 47 publications

Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization

Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization

Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain

Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons

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