Histamine-induced itch converts into pain in neuropathic hyperalgesia.

Physiologically, itch and pain are transmitted in separate specific peripheral C-units and central afferent pathways. Some neuropathic pain patients with intact but sensitized (irritable) primary C-nociceptors have spontaneous pain, heat hyperalgesia, static and dynamic mechanical hyperalgesia. The question was whether cutaneous histamine application induces pain in these patients. For comparison histamine was applied into normal skin experimentally sensitized by capsaicin. Histamine application in the capsaicin-induced primary or secondary hyperalgesic skin did not change the intensity and quality of capsaicin pain. Itch was profoundly inhibited. Conversely, histamine application in neuropathic skin induced severe increase in spontaneous burning pain but no itch. In neuropathies irritable nociceptors may express histamine receptors or induce central sensitization to histaminergic stimuli so that itch converts into pain.     

Immune and inflammatory mechanisms in neuropathic pain

Tissue damage, inflammation or injury of the nervous system may result in chronic neuropathic pain characterised by increased sensitivity to painful stimuli (hyperalgesia), the perception of innocuous stimuli as painful (allodynia) and spontaneous pain. Neuropathic pain has been described in about 1% of the US population, is often severely debilitating and largely resistant to treatment. Animal models of peripheral neuropathic pain are now available in which the mechanisms underlying hyperalgesia and allodynia due to nerve injury or nerve inflammation can be analysed. Recently, it has become clear that inflammatory and immune mechanisms both in the periphery and the central nervous system play an important role in neuropathic pain. Infiltration of inflammatory cells, as well as activation of resident immune cells in response to nervous system damage, leads to subsequent production and secretion of various inflammatory mediators. These mediators promote neuroimmune activation and can sensitise primary afferent neurones and contribute to pain hypersensitivity. Inflammatory cells such as mast cells, neutrophils, macrophages and T lymphocytes have all been implicated, as have immune-like glial cells such as microglia and astrocytes. In addition, the immune response plays an important role in demyelinating neuropathies such as multiple sclerosis (MS), in which pain is a common symptom, and an animal model of MS-related pain has recently been demonstrated. Here, we will briefly review some of the milestones in research that have led to an increased awareness of the contribution of immune and inflammatory systems to neuropathic pain and then review in more detail the role of immune cells and inflammatory mediators.     

Pathophysiological mechanisms of neuropathic pain

Neurological Sciences - It is largely acknowledged that multiple and complex pathophysiological mechanisms may be at play in neuropathic pain. This short review summarises the current understanding...     

Endothelin-1-induced pain and hyperalgesia: a review of pathophysiology, clinical manifestations and future therapeutic options

Pain in patients with metastatic cancer contributes to increased suffering in those already burdened by their advancing illness. The causes of this pain are unknown, but are likely to involve the action of tumour-associated mediators and their receptors. In recent years, several chemical mediators have increasingly come to the forefront in the pathophysiology of cancer pain. One such mediator, endothelin-1 (ET-1), is a peptide of 21 amino acids that was initially shown to be a potent vasoconstrictor. Extensive research has revealed that members of the ET family are indeed produced by several epithelial cancerous tumours, in which they act as autocrine and/or paracrine growth factors. Several preclinical and clinical studies of various malignancies have suggested that the ET axis may represent an interesting contributor to tumour progression. In addition, evidence is accumulating to suggest that ET-1 may contribute to pain states both in humans and in other animals. ET-1 both stimulates nociceptors and sensitises them to painful stimuli. Selective stimulation of ET receptors has been implicated as a cause of inflammatory, neuropathic and tumoural pain. ET-1-induced pain-related behaviour seems to be mediated either solely by one receptor type or via both endothelin-A receptors (ETAR) and endothelin-B receptors (ETBR). Whereas stimulation of ETAR on nociceptors always elicits a pain response, stimulation of ETBR may cause analgesia or elicit a pain response, depending on the conditions. The administration of ETAR antagonists in the receptive fields of these nociceptors has been shown to ameliorate pain-related behaviours in animals, as well as in some patients with advanced metastatic prostate cancer. The identification of tumour-associated mediators that might directly or indirectly cause pain in patients with metastatic disease, such as ET-1, should lead to improved, targeted analgesia for patients with advanced cancer. In this review, we will describe the current status of the role of ET-1 in different types of painful syndromes, with special emphasis on its role in the pathophysiology of cancer pain. Finally, potential new treatment options that are based on the role of the ET axis in the pathophysiology of cancer are elaborated.     

鞘内注射催产素对大鼠神经痛反应的影响

目的 :观察不同剂量催产素对神经痛大鼠热痛敏的影响。方法 :在脊神经结扎致坐骨神经损伤大鼠模型上采用辐射热缩腿反射的方法 ,以抬脚潜伏期作为观察指标。结果 :蛛网膜下腔注射催产素 (1ng ,2 5ng ,5ng)对神经痛大鼠有镇痛作用 ,呈剂量相关关系。结论 :鞘内注射催产素对神经痛大鼠有镇痛作用。     

Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations

Chronic neuropathic pain, caused by lesions in the peripheral or central nervous system, comes in many forms. We describe current approaches to the diagnosis and assessment of neuropathic pain and discuss the results of recent research on its pathophysiologic mechanisms. Randomized controlled clinical trials of gabapentin, the 5% lidocaine patch, opioid analgesics, tramadol hydrochloride, and tricyclic antidepressants provide an evidence-based approach to the treatment of neuropathic pain, and specific recommendations are presented for use of these medications. Continued progress in basic and clinical research on the pathophysiologic mechanisms of neuropathic pain may make it possible to predict effective treatments for individual patients by application of a pain mechanism-based approach.     

Telmisartan inhibits hyperalgesia and inflammatory progression in a diabetic neuropathic pain model of Wistar rats

Objective:

To evaluate the potential therapeutic value of telmisartan (TMT) against diabetic neuropathy (DN) and associated pain in Wistar rats.

Methods:

Peripheral DN was induced by a single intraperitoneal streptozotocin injection (55 mg/kg), and 3 weeks later TMT treatment was started (5 and 10 mg/kg/day), and continued for 4 weeks. Mechanical nociceptive threshold, motor coordination, and thermal nociceptive threshold tests were performed before and after TMT treatment. In serum, glucose, pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6 were assessed. Nerve growth factor (NGF) levels and histopathological changes were estimated in the sciatic nerve. This study was conducted at the Experimental Animal Care Center, Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia between January 2013 and May 2014.

Results:

We observed a significant reduction in mechanical nociceptive threshold, motor coordination, and thermal nociceptive threshold in diabetic animals. The TMT treatment significantly enhanced the reduced mechanical nociceptive threshold. The untreated diabetic animals revealed a significant decrease in sciatic NGF, which was markedly attenuated by TMT. The elevated serum levels of cytokines in diabetic animals were inhibited by the TMT treatments. Histopathological evaluation showed obvious nerve degeneration in the diabetic group that was eliminated in the TMT treated diabetic groups.

Conclusion:

Telmisartan has a potential neuro-protective effect on peripheral DN; this is mediated through its anti-inflammatory effects and its dual properties as an angiotensin receptor blocker, and a partial peroxisome proliferator activator receptor-g ligand.Worldwide, diabetic neuropathy (DN) is a major complication of diabetes mellitus. It affects around 15-25% in type-1, and 30-40% in type-2 diabetic patients, causing disabilities, and a high mortality rate. Neuropathic pain defined as a form of chronic pain resulting from damage or abnormal function of the central or peripheral nervous system.1 Patients with neuropathic pain frequently report sensory abnormalities such as burning sensations, hyperalgesia, allodynia, and dysesthesia.2 Diabetic neuropathy can also alter the patient’s quality of life by interfering with emotional well-being, which represents a challenge for clinicians because of its severity, chronicity, and resistance to some classical analgesics.3 The behavioral responses of diabetic rodents to thermal and mechanical hyper- and hypoalgesia as well as tactile allodynia to external stimuli have led to the identification of several mechanisms of abnormal sensation and pain in diabetes. It is confirmed that DN is characterized by neuronal degeneration and marked alterations in neural growth factors such as nerve growth factor (NGF) and insulin-like growth factor (IGF).4 Despite the availability of therapies to alleviate the symptoms of DN, a limited number of medications are available to control its basic causes. Diabetic associated disability and premature mortality are also caused by vascular complications, and several observational reports suggest the potential benefits of intensive blood pressure lowering of diabetic patients.5 The use of angiotensin converting enzyme inhibitors (ACEI) or an angiotensin receptor blocker (ARB) is recommended by current hypertension guidelines for patients with diabetes to achieve a target blood pressure level of 130/80 mm Hg or lower.5 The correlation between the renin angiotensin system and diabetic complications has been observed. Besides being clinically effective in diabetic nephropathy, ACEI or ARBs can improve nerve conduction deficit during peripheral DN in both animal models and human clinical studies. Furthermore, it has been suggested that ARBs are beneficial for nerve regeneration deficits in peripheral DN.6,7 Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that activates cellular metabolism leading to cellular growth and differentiation,8 and improved insulin sensitivity.9 The beneficial effects of PPAR-γ ligands were demonstrated in experimental DN by suppressing the angiotensin type receptor 1 (AT1R) expression.10 The PPAR-γ ligands also have anti-inflammatory and antioxidant properties, which are known to be beneficial for microvascular complications in diabetes.9 Telmisartan (TMT) (Micardis^®) is one of the most widely used antihypertensives for diabetic patients. It is an ARB with a nephro-protective11 and neuro-protective effect against retinal inflammation.12 Recently, we reported that TMT increases the levels of neurotrophic factors, endogenous antioxidants, and reduces the signs of apoptosis efficiently in diabetic retina.13 The present study was designed to investigate the potential neuro-protective effects of TMT (Micardis^®) in a Wistar rat model of peripheral DN of streptozotocin-induced diabetes.     

Allodynia and hyperalgesia evoked by sciatic mononeuropathy in NKI receptor knockout mice

We have examined the participation of NK1 receptors in neuropathic pain by comparing behavioural responses after partial sciatic nerve ligation in wild-type (WT) and NK1 receptor knockout (KO) mice. Mechanical responses were tested with von Frey hairs, and cooling responses with acetone. WT and KO mice showed similar reactions before surgery. Nerve-ligated WT and KO mice showed equivalent spontaneous pain-related behaviour. Mechanical (mean threshold 20 +/- vs 9 +/- 1 mN) and cold allodynia (61 +/- vs 14 +/- 2 behaviours evoked by acetone) were significantly greater than in sham animals, but similar in WT and KO mice. We conclude that NK1 receptors are not essential for mechanical and cold allodynia evoked by partial nerve ligation.     

Long-term intrathecal administration of glycine prevents mechanical hyperalgesia in a rat model of neuropathic pain

Neuropathic pain has been postulated to be mediated, in part, by amino acid neurotransmitters including glycine. The current study examined the effects of continuous intrathecal glycine administration (0.1 mumol 0.5 microliter-1 h-1) on the development of mechanical hyperalgesia and other features of neuropathic pain evoked by unilateral loose ligation of the sciatic nerve in the rat. Each hind paw was tested for withdrawal threshold to mechanical stimuli prior to, and after ligation at intervals of 3, 6, 9, 12 and 16 days. Pain behavior (posture and gait) and hind paw dystrophic features (redness and swelling) were also examined. Glycine increased the normal mechano-nociceptive responses and prevented the development of mechano-nociceptive hyperalgesia. Spontaneous nociceptive behavior and hind paw dystrophic features, seen in the saline treated rats, were significantly diminished. Our results suggest that spinal cord inhibitory glycinergic activity is important for normal mechano-receptive responsitivity and development of mechano-nociceptive hyperalgesia in this model.     

Molecular mechanisms underlying the effects of acupuncture on neuropathic pain

Acupuncture has been used to treat neuropathic pain for a long time, but its mechanisms of action remain unknown. In this study, we observed the effects of electroacupuncture and manual acu-puncture on neuropathic pain and on ephrin-B/EphB signaling in rats models of chronic constriction injury-induced neuropathic pain. The results showed that manual acupuncture and elec-puncture significantly reduced mechanical hypersensitivity following chronic constriction injury, es-pecially electroacupuncture treatment. Real-time PCR results revealed that ephrin-B1/B3 and EphB1/B2 mRNA expression levels were significantly increased in the spinal dorsal horns of chronic constriction injury rats. Electroacupuncture and manual acupuncture suppressed the high sion of ephrin-B1 mRNA, and elevated EphB3/B4 mRNA expression. Electroacupuncture signifi-cantly enhanced the mRNA expression of ephrin-B3 and EphB3/B6 in the dorsal horns of neuro-pathic pain rats. Western blot results revealed that electroacupuncture in particular, and manual acupuncture, significantly up-regulated ephrin-B3 protein levels in rat spinal dorsal horns. The re-sults of this study suggest that acupuncture could activate ephrin-B/EphB signaling in neuropathic pain rats and improve neurological function.     

The roles of sodium channels in nociception: implications for mechanisms of neuropathic pain

Animal models have provided useful insights into the development and treatment of neuropathic pain. New genetic data from both human studies and transgenic mouse models suggest that specific voltage-gated sodium channel subtypes are associated with specific types of pain and, as such, may be useful analgesic drug targets for a variety of pain types including neuropathic pain. Global voltage-gated sodium channel blockers such as lidocaine have proven efficacy in treating pain but can be limited by adverse effects when administered systemically. Selective sodium channel blockers targeting channels at the periphery (Nav1.7, Nav1.8, and Nav1.9) could potentially reduce the side effect profile. Individual isoforms of voltage-gated sodium channels have been linked to particular types of pain. Nav1.7 is a useful target for ameliorating acute mechanical pain and inflammatory pain, and strong evidence also suggests that Nav1.9 could be targeted for treating inflammatory pain. Selective blockers of Nav1.8 could also have clinical benefit for visceral pain. Although there is no association between a single sodium channel isoform and neuropathic pain, combined blockade of peripherally expressed isoforms Nav1.7, Nav1.8, and Nav1.9 may prove useful.     

Quercetin, a bioflavonoid, attenuates thermal hyperalgesia in a mouse model of diabetic neuropathic pain

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, has been recognised as one of the most difficult types of pain to treat. Lack of understanding of etiology involved, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve pain. The aim of the present study was to explore the antinociceptive effect of a bioflavonoid, quercetin, both in control and streptozotocin (STZ)-induced diabetic mice. After 4 weeks of a single intraperitoneal injection of STZ (200 mg/kg), both control and diabetic mice were subjected to test thermal hyperalgesia by tail-immersion assay (warm water). Diabetic mice exhibited a significant hyperalgesia as compared with control mice. Quercetin (100 but not 50 mg/kg p.o.) produced a marked increase in tail-flick latencies in both diabetic and nondiabetic mice. Quercetin-induced increase in nociceptive threshold was reversed by naloxone (2 mg/kg i.p.), an opioid receptor antagonist. These preliminary results indicate an antinociceptive activity of quercetin, probably through modulation of opioidergic mechanism and point towards its potential to attenuate diabetic neuropathic pain.     

Intrathecal transplantation of neuroblastoma cells decreases heat hyperalgesia and cold allodynia in a rat model of neuropathic pain

Intrathecal grafting of cells as biological pumps to deliver monoamines, endorphins, and/or trophic factors, has been shown to be effective in treating chronic pain both in experimental animals and in clinical trials. We have tested whether intrathecal implantation of neuroblastoma cells reduces heat hyperalgesia and cold allodynia in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Behavioral tests and cerebrospinal fluid (CSF) collection were performed before CCI, 1 week later (after which, vehicle or NB69 cells were intrathecally injected) and at 4, 7, and 14 days post-injection. Both CSF sampling and injection of the cells were performed by direct lumbar puncture. Intrathecal grafting of 4 x 10(6) NB69 neuroblastoma cells reduced to basal levels the nociceptive response to heat in nerve-injured hindpaws, while the response of control limbs remained unchanged. Similarly, the allodynic response to cold elicited by acetone evaporation decreased in the animals implanted with NB69 cells. An increase in the concentrations of dopamine and serotonin metabolites of around 150% was observed in the CSF of animals that received grafts of NB69 cells. These data suggest that the monoamines released by NB69 cells in the intrathecal space produce analgesia to neuropathic pain in rats.     

SYM-2081 a kainate receptor antagonist reduces allodynia and hyperalgesia in a freeze injury model of neuropathic pain

Cold-freeze injury at -4 degrees C to the rat sciatic nerve produces mechanical allodynia and thermal hyperalgesia [M.A. Kleive, P.S. Jungbluth, J.A. Uhlenkamp, K.C. Kajander, Cold injury to rat sciatic nerve induces thermal hyperalgesia or analgesia, 8th World Congress on Pain, Vancouver, BC, Canada, August 1996 (Abstract).]. The NMDA receptor, an excitatory amino acid (EAA) receptor, appears to be involved in the development of allodynia and hyperalgesia following nerve injury. The role, if any, of the kainate receptor, another EAA receptor, remains unknown. In the current study, we evaluated whether (2S,4R)-4-methylglutamic acid (SYM-2081), a recently developed kainate receptor antagonist, attenuates increased responsiveness following cold injury to the sciatic nerve. During baseline testing, Sprague-Dawley rats were evaluated for frequency of withdrawal from von Frey filaments and latency of withdrawal from a radiant thermal source. Animals were then anesthetized, the left sciatic nerve was exposed, and the nerve was cooled to -4 degrees C for 15 min (n=24). For control rats (n=24), all procedures were identical except that the nerve was maintained at 37 degrees C. Testing resumed on the third day following surgery. On the fifth post-operative day, SYM-2081 (150 or 100 mg/kg), fentanyl citrate (0. 04 mg/kg) or vehicle was injected intraperitoneally. Injury to the rat sciatic nerve induced a significant increase in withdrawal frequency and a significant decrease in withdrawal latency (ANOVA, p<0.05). SYM-2081 and fentanyl significantly reduced these responses (p<0.05). These results suggest that kainate and opioid receptors are involved in the mechanical allodynia and thermal hyperalgesia that develop following cold injury to the sciatic nerve.     

Investigating the possible pain attenuating mechanisms of pregabalin in chronic constriction injury-induced neuropathic pain in rats

Abstract

Aim of the study: The current study was aimed to investigate the neuropathic pain attenuating mechanism of pregabalin using chronic constriction injury (CCI) model in rats.

Material and Methods: The sciatic nerve was ligated by placing four loose ligatures around it to induce neuropathic pain. The pain development in terms of cold allodynia, mechanical hyperalgesia, and heat hyperalgesia was assessed on the 7th and 14th day after surgery, using acetone drop, pinprick, and hot plate tests. On the 14th day after the injury, pain parameters were assessed 30?minutes after administration of pregabalin (30?mg/kg) and sodium nitroprusside (5?mg/kg) in CCI-subjected rats.

Results: CCI led to induction of neuropathic pain, which was more prominent on 14th day in comparison to 7th day. A single administration of pregabalin and sodium nitroprusside on 14th day, markedly reduced pain parameters and increased serum nitrite levels. Pretreatment with L-NAME abolished neuropathic pain attenuating effects of pregabalin suggesting that pregabalin may increase the levels of nitric oxide to mitigate neuropathic pain. Pretreatment with naloxone significantly abrogated pain attenuating effects of pregabalin and sodium nitroprusside in CCI-subjected rats suggesting that pregabalin and nitric oxide-mediated analgesic action are mediated through release of endogenous opioids. Moreover, naloxone failed to modulate pregabalin-induced increase in nitric oxide levels suggesting that the opioid system does not control the nitric oxide levels, and opioids may be downstream modulators of nitric oxide.

Conclusion: Pregabalin may increase the release of nitric oxide, which may increase the release of endogenous opioids to attenuate neuropathic pain in CCI subjected rats.     

A role for the TTX-resistant sodium channel Nav 1.8 in NGF-induced hyperalgesia, but not neuropathic pain

The tetrodotoxin-resistant voltage-gated sodium channel Nav 1.8 is expressed only in nociceptive sensory neurons. This channel has been proposed to contribute significantly to the sensitization of primary sensory neurons after injury. We have studied the nociceptive behaviours of mice carrying a null mutation in the Nav 1.8 gene (Nav 1.8 -/-) in models of peripheral inflammation as well as a model of neuropathic pain. The results from the present studies reveal that Nav 1.8 is a necessary mediator of NGF-induced thermal hyperalgesia but is not essential for PGE2-evoked hypersensitivity. Neuropathic pain behaviours were unchanged in Nav 1.8 -/- mice indicating that this channel is not involved in the alteration of sensory thresholds following peripheral nerve injury.