Cellular and Molecular Mechanisms of Pain

Basbaum, Allan I.; Bautista, Diana M.; Scherrer, Grégory; Julius, David

doi:10.1016/j.cell.2009.09.028

Cited by 3,415 publications

(3,320 citation statements)

References 162 publications

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“…In our study the Aδ‐fibres were selected because main behavioural changes are related to tactile allodynia and hyperalgesia and they respond to mechanical stimulation (Basbaum et al., 2009) even better than C‐fibres. Our aim was to electrophysiologically study the changes in Aδ‐fibre activity and to determine if these changes were sensitive to the treatment with the σ1R antagonist.…”

Section: Discussionmentioning

confidence: 95%

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats

Paniagua

Girón

Goicoechea

et al. 2016

European Journal of Pain

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BackgroundE‐52862 (S1RA, 4‐[2‐[[5‐methyl‐1‐(2‐naphthalenyl)‐1H‐pyrazol‐3‐yl]oxy]ethyl]‐morpholine), a novel selective sigma 1 receptor (σ1R) antagonist, has demonstrated efficacy in nociceptive and neuropathic pain models. Our aim was to test if σ1R blockade with E‐52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model.MethodsMechanical and thermal response thresholds were tested on 7‐, 13‐, 14‐ and 15‐week‐old ZDF rats treated with saline or with E‐52862 acutely administered on week 13, followed by sub‐chronic administration (14 days). Axonal peripheral activity (skin–saphenous nerve preparation) and isolated aorta or mesenteric bed reactivity were analysed in 15‐week‐old ZDF rats treated with saline or E‐52862 and in LEAN rats.ResultsZucker diabetic fatty rats showed significantly decreased thermal withdrawal latency and threshold to mechanical stimulation on week 13 compared to week 7 (prediabetes) and with LEAN animals; single‐dose and sub‐chronic E‐52862 administration restored both parameters to those recorded on week 7. Regarding axonal peripheral activity, E‐52862 treatment increased the mean mechanical threshold (77.3 ± 21 mN vs. 19.6 ± 1.5 mN, saline group) and reduced the response evoked by mechanical increasing stimulation (86.4 ± 36.5 vs. 352.8 ± 41.4 spikes) or by repeated mechanical supra‐threshold steps (39.4 ± 1.4 vs. 83.5 ± 0.9). E‐52862 treatment also restored contractile response to phenylephrine in aorta and mesenteric bed.ConclusionsE‐52862 administration reverses neuropathic (behavioural and electrophysiological) and vascular signs in the ZDF rat.SignificanceBlockade of σ1R avoids the development of diabetic neuropathy in rats, and may represent a potentially useful therapeutic approach to peripheral neuropathies in diabetic patients.What does this study add? This study presents evidences for the potential usefulness of sigma receptor blockade on diabetic neuropathy in rats.The methodology includes behavioural evidences, electrophysiological data and vascular‐isolated models.

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Section: Discussionmentioning

confidence: 95%

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats

Paniagua

Girón

Goicoechea

et al. 2016

European Journal of Pain

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“…Moreover, the close proximity of macrophages and nerves within lesions suggests that macrophage-derived cytokines may also contribute to pelvic pain in endometriosis by acting directly on nociceptors generating a pain response and hypersensitivity. 40,42 We have previously shown that estrogens can also act directly on human sensory neurons to increase the mRNA concentrations of key nociceptive ion channels, including TAC1, P2RX3, and TRPV1, 43 further supporting a role for estrogens in modulating pain response in endometriosis by acting on nerves.…”

Section: Endometriosis Is a Neuroinflammatory Disordermentioning

confidence: 91%

“…39 Macrophages are vital in the regeneration of damaged nerves after injury to the central nervous system and peripheral nervous system and, although infiltrating sensory nerves present within endometriosis lesions are not damaged per se, they may experience a chemical milieu similar to inflammation in response to trauma. 40 In a mouse model of acute peripheral nerve injury, an alternative macrophage response was detected, 41 and this phenotype has been associated with a sterile inflammatory environment similar to endometriosis. We suggest that the reciprocal relationship between macrophages and nerves encourages innervation of endometriosis lesions.…”

Section: Endometriosis Is a Neuroinflammatory Disordermentioning

confidence: 99%

Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis

Greaves

Temp

Esnal-Zufiurre

et al. 2015

The American Journal of Pathology

141

121

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Endometriosis occurs in approximately 10% of women and is associated with persistent pelvic pain. It is defined by the presence of endometrial tissue (lesions) outside the uterus, most commonly on the peritoneum. Peripheral neuroinflammation, a process characterized by the infiltration of nerve fibers and macrophages into lesions, plays a pivotal role in endometriosis-associated pain. Our objective was to determine the role of estradiol (E2) in regulating the interaction between macrophages and nerves in peritoneal endometriosis. By using human tissues and a mouse model of endometriosis, we demonstrate that macrophages in lesions recovered from women and mice are immunopositive for estrogen receptor b, with up to 20% being estrogen receptor a positive. In mice, treatment with E2 increased the number of macrophages in lesions as well as concentrations of mRNAs encoded by Csf1, Nt3, and the tyrosine kinase neurotrophin receptor, TrkB. By using in vitro models, we determined that the treatment of rat dorsal root ganglia neurons with E2 increased mRNA concentrations of the chemokine C-C motif ligand 2 that stimulated migration of colony-stimulating factor 1edifferentiated macrophages. Conversely, incubation of colony-stimulating factor 1 macrophages with E2 increased concentrations of brainderived neurotrophic factor and neurotrophin 3, which stimulated neurite outgrowth from ganglia explants. In summary, we demonstrate a key role for E2 in stimulating macrophage-nerve interactions, providing novel evidence that endometriosis is an estrogen-dependent neuroinflammatory disorder. Endometriosis affects 10% of reproductive age women and is associated with persistent pelvic pain. 1 It is defined by the presence of endometrial-like tissue (lesions) found outside the uterus, most commonly on the peritoneum. The mechanisms underlying endometriosis-associated pain are poorly understood, but it has been postulated that estrogen-dependent neuroinflammation may be involved. 2 Notably, the presence of endometrial tissue fragments on the peritoneum elicits an immune response, including recruitment of macrophages, 3 blood vessels, and nerve fibers into the resultant lesions. 4,5 Within the lesions, CD68 þ macrophages have been detected in close association with nerve fibers. 6 Studies investigating macrophage activation and recruitment have revealed that endometriosis-associated macrophages exhibit a phenotype consistent with the alternative end of the macrophage activation spectrum. 7,8 In a mouse model of endometriosis that included cell transfer of polarized macrophages, Bacci et al 7 reported that mice injected with proinflammatory macrophages [macrophage (interferon g)] developed microscopic lesions, but those injected with alternatively activated macrophages [macrophage (IL-4)] developed larger lesions with a well-developed vasculature. Our studies in a mouse model of endometriosis have revealed that macrophages resident in peritoneal lesions can originate from both the peritoneum and the endometrium. 9

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“…The ability to detect and react to noxious environmental stimuli is a highly adaptive physiological response that is mediated through the coordinated processing of sensory information by the peripheral and central nervous systems [1][2][3][4]. Chronic pain in the presence or absence of tissue trauma is characterized by increased sensitivity to painful stimuli (i.e., hyperalgesia) and the perception of pain in response to normally innocuous stimuli (i.e., allodynia) [4].…”

Section: Introductionmentioning

confidence: 99%

“…Chronic pain in the presence or absence of tissue trauma is characterized by increased sensitivity to painful stimuli (i.e., hyperalgesia) and the perception of pain in response to normally innocuous stimuli (i.e., allodynia) [4]. Based on many studies of the neurobiology of pain over the last 20 years, it is now appreciated that both peripheral and central neural pathways become "sensitized" in response to ongoing nociceptor stimulation [3].…”

Section: Introductionmentioning

confidence: 99%

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

Gum

Wakefield

Jarvis

2011

Purinergic Signalling

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Enhanced sensitivity to noxious stimuli and the perception of non-noxious stimuli as painful are hallmark sensory perturbations associated with chronic pain. It is now appreciated that ATP, through its actions as an excitatory neurotransmitter, plays a prominent role in the initiation and maintenance of chronic pain states. Mechanistically, the ability of ATP to drive nociceptive sensitivity is mediated through direct interactions at neuronal P2X3 and P2X2/3 receptors. Extracellular ATP also activates P2X4, P2X7, and several P2Y receptors on glial cells within the spinal cord, which leads to a heightened state of neural-glial cell interaction in ongoing pain states. Following the molecular identification of the P2 receptor superfamilies, selective small molecule antagonists for several P2 receptor subtypes were identified, which have been useful for investigating the role of specific P2X receptors in preclinical chronic pain models. More recently, several P2X receptor antagonists have advanced into clinical trials for inflammation and pain. The development of orally bioavailable blockers for ion channels, including the P2X receptors, has been traditionally difficult due to the necessity of combining requirements for target potency and selectivity with suitable absorption distribution, metabolism, and elimination properties. Recent studies on the physicochemical properties of marketed orally bioavailable drugs, have identified several parameters that appear critical for increasing the probability of achieving suitable bioavailability, central nervous system exposure, and acceptable safety necessary for clinical efficacy. This review provides an overview of the antinociceptive pharmacology of P2X receptor antagonists and the chemical diversity and drug-like properties for emerging antagonists of P2X3, P2X2/3, P2X4, and P2X7 receptors. Keywords

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Cellular and Molecular Mechanisms of Pain

Cited by 3,415 publications

References 162 publications

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats

Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

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