Antiallodynic Effects Research Articles

Anti-oxidant profile of Divya-Peedantak-Vati abates paclitaxel-induced hyperalgesia and allodynia in CD-1 mice model of neuropathic pain

BackgroundPaclitaxel (PTX) is a known chemotherapeutic agent, used to treat different types of cancers. However, it leads to neuropathic pain in a sizeable proportion of the patients. Currently, analgesics, opioids, tricyclic antidepressants and anticonvulsants are prescribed for PTX-mediated chemotherapy-induced peripheral neuropathy (CIPN). However, these treatments have acute side-effects, creating a need for safer alternative treatment option. MethodPTX-mediated CIPN has nociceptive outcomes, like, allodynia and hyperalgesia with an underlying inflammatory and oxidative causes. The herbo-mineral medicine, Divya-Peedantak-Vati (DPV) is known for its effectivity against joint pain and inflammatory disorders in Ayurveda, a traditional Indian system of medicine. Therefore, anti-neuropathic potential of DPV was assessed in PTX-induced neuropathic CD-1 mice, with allodynia and hyperalgesia, as the clinically relevant endpoints. DPV was investigated for its nociception-modulatory and anti-inflammatory effects under in vivo and in vitro conditions. ResultsDPV treatment exhibited notable anti-allodynic and anti-hyperalgesic effects in a dose dependent manner, and displayed prominent anti-oxidant effects in the sciatic nerve of the study animals. It also moderated, in a dose dependent manner, the levels of cytokine, interleukin-1beta (IL-1β) and tumor necrosis factor alpha (TNF-α) induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. ConclusionsThe novelty of this study lies in the demonstration of the anti-neuropathic potential and elucidation of anti-neuropathic mode-of-action of an herbal medicine. Taken together, this study showed that DPV could well be an effective alternative healing option for PTX-mediated CIPN.

Relief of neuropathic pain by cell-specific manipulation of nucleus accumbens dopamine D1- and D2-receptor-expressing neurons

Emerging evidence suggests that the mesolimbic dopaminergic network plays a role in the modulation of pain. As chronic pain conditions are associated with hypodopaminergic tone in the nucleus accumbens (NAc), we evaluated the effects of increasing signaling at dopamine D1/D2-expressing neurons in the NAc neurons in a model of neuropathic pain induced by partial ligation of sciatic nerve. Bilateral microinjection of either the selective D1-receptor (Gs-coupled) agonist Chloro-APB or the selective D2-receptor (Gi-coupled) agonist quinpirole into the NAc partially reversed nerve injury-induced thermal allodynia. Either optical stimulation of D1-receptor-expressing neurons or optical suppression of D2-receptor-expressing neurons in both the inner and outer substructures of the NAc also transiently, but significantly, restored nerve injury-induced allodynia. Under neuropathic pain-like condition, specific facilitation of terminals of D1-receptor-expressing NAc neurons projecting to the VTA revealed a feedforward-like antinociceptive circuit. Additionally, functional suppression of cholinergic interneurons that negatively and positively control the activity of D1- and D2-receptor-expressing neurons, respectively, also transiently elicited anti-allodynic effects in nerve injured animals. These findings suggest that comprehensive activation of D1-receptor-expressing neurons and integrated suppression of D2-receptor-expressing neurons in the NAc may lead to a significant relief of neuropathic pain.

GPR55 and GPR119 Receptors Contribute to the Processing of Neuropathic Pain in Rats.

Orphan G-protein-coupled receptors (GPCR) comprise a large number of receptors which are widely distributed in the nervous system and represent an opportunity to identify new molecular targets in pain medicine. GPR55 and GPR119 are two orphan GPCR receptors whose physiological function is unclear. The aim was to explore the participation of spinal GPR55 and GPR119 in the processing of neuropathic pain in rats. Mechanical allodynia was evaluated using von Frey filaments. Protein localization and modulation were measured by immunohistochemistry and western blotting, respectively. Intrathecal administration of CID16020046 (selective GPR55 antagonist) or AS1269574 (selective GPR119 agonist) produced a dose-dependent antiallodynic effect, whereas O1062 (GPR55 agonist) and G-protein antagonist peptide dose-dependently prevented the antiallodynic effect of CID16020046 and AS1269574, respectively. Both GPR55 and GPR119 receptors were expressed in spinal cord, dorsal root ganglia and sciatic nerve, but only GPR119 was downregulated after 14 days of spinal nerve ligation. Data suggest that GPR55 and GPR119 participate in the processing of neuropathic pain and could be useful targets to manage neuropathic pain disorders.

TNF-α-Mediated RIPK1 Pathway Participates in the Development of Trigeminal Neuropathic Pain in Rats.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) participates in the regulation of cellular stress and inflammatory responses, but its function in neuropathic pain remains poorly understood. This study evaluated the role of RIPK1 in neuropathic pain following inferior alveolar nerve injury. We developed a model using malpositioned dental implants in male Sprague Dawley rats. This model resulted in significant mechanical allodynia and upregulated RIPK1 expression in the trigeminal subnucleus caudalis (TSC). The intracisternal administration of Necrosatin-1 (Nec-1), an RIPK1 inhibitor, blocked the mechanical allodynia produced by inferior alveolar nerve injury The intracisternal administration of recombinant rat tumor necrosis factor-α (rrTNF-α) protein in naive rats produced mechanical allodynia and upregulated RIPK1 expression in the TSC. Moreover, an intracisternal pretreatment with Nec-1 inhibited the mechanical allodynia produced by rrTNF-α protein. Nerve injury caused elevated TNF-α concentration in the TSC and a TNF-α block had anti-allodynic effects, thereby attenuating RIPK1 expression in the TSC. Finally, double immunofluorescence analyses revealed the colocalization of TNF receptor and RIPK1 with astrocytes. Hence, we have identified that astroglial RIPK1, activated by the TNF-α pathway, is a central driver of neuropathic pain and that the TNF-α-mediated RIPK1 pathway is a potential therapeutic target for reducing neuropathic pain following nerve injury.

Effect of Pregabalin and Gabapentin on Nociceptive Behaviors Induced by Spinal Nerve Ligation

Pain is defined as an unpleasant sensory and emotional experience, associated with actual or potential tissue damage. According to its neurobiological mechanism, pain is classified into nociceptive, inflammatory, dysfunctional, and neuropathic. Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory nervous system. Both pregabalin and gabapentin are pharmaceuticals used as validation drugs in experimental models of NP. Pregabalin was shown to produce significant antihyperalgesic and antiallodynic effects. Gabapentin is used as a reference compound for new analgesics and reduces tactile allodynia in rats. The aim of this work is to evaluate pregabalin and gabapentin effects on nociceptive behaviors induced by spinal nerve ligation (SNL). Female Wistar rats of 140 - 160 g were used, divided into five groups: Naive, SHAM, SNL rats treated with saline solution, SNL rats treated with pregabalin 30 mg/kg p.o., SNL rats treated with gabapentin 300 mg/kg p.o. Nociceptive behaviors were determined by the up and down method. In the establishment of SNL-induced allodynic behavior, a reduction in paw withdrawal threshold was observed in the time course, which was present from day 1 and it was maintained for 28 days post-ligation. With the administration of pregabalin and gabapentin, anti-allodynic behavior was observed in the time course and in the areas under the curve (AUC) of the time course of anti-allodynic behavior, significant difference was observed between pregabalin, and gabapentin groups compared to vehicle with a value of p < 0.0001. The results showed pregabalin and gabapentin induce an antinociceptive effect in rats subjected to SNL.

Title: Novel Analgesic Potential of ß2-Agonists for Neuropathic Pain via ß2-Agonist Action.

Multimodal therapies are often employed to treat chronic pain, and ß2-agonists are a potential drug class that shows promise. The primary aim of this paper is to discuss the role of ß2-agonists as an adjunctive therapy for chronic pain based on the current literature. Recent studies in mouse models have shown that the ß2-adrenergic system plays an essential role in the analgesic properties of antidepressant drugs used to treat neuropathic pain and that the adrenergic relies on an intact endogenous opioid system to be effective. Studies also show that ß2-agonism alone is adequate to exert anti-allodynic effects in a mouse model. This paper summarized the basic physiology and pharmacology of the sympathetic nervous system and specifically the ß2-adrenergic system and summarized current literature in its involvement in the treatment of chronic neuropathic pain.

Hydrogen Sulfide Inhibits Inflammatory Pain and Enhances the Analgesic Properties of Delta Opioid Receptors.

Chronic inflammatory pain is present in many pathologies and diminishes the patient’s quality of life. Moreover, most current treatments have a low efficacy and significant side effects. Recent studies demonstrate the analgesic properties of slow-releasing hydrogen sulfide (H2S) donors in animals with osteoarthritis or neuropathic pain, but their effects in inflammatory pain and related pathways are not completely understood. Several treatments potentiate the analgesic actions of δ-opioid receptor (DOR) agonists, but the role of H2S in modulating their effects and expression during inflammatory pain remains untested. In C57BL/6J male mice with inflammatory pain provoked by subplantar injection of complete Freund’s adjuvant, we evaluated: (1) the antiallodynic and antihyperalgesic effects of different doses of two slow-releasing H2S donors, i.e., diallyl disulfide (DADS) and phenyl isothiocyanate (P-ITC) and their mechanism of action; (2) the pain-relieving effects of DOR agonists co-administered with H2S donors; (3) the effects of DADS and P-ITC on the oxidative stress and molecular changes caused by peripheral inflammation. Results demonstrate that both H2S donors inhibited allodynia and hyperalgesia in a dose-dependent manner, potentiated the analgesic effects and expression of DOR, activated the antioxidant system, and reduced the nociceptive and apoptotic pathways. The data further demonstrate the possible participation of potassium channels and the Nrf2 transcription factor signaling pathway in the pain-relieving activities of DADS and P-ITC. This study suggests that the systemic administration of DADS and P-ITC and local application of DOR agonists in combination with slow-releasing H2S donors are two new strategies for the treatment of inflammatory pain.

Intrathecal IGF2 siRNA injection provides long-lasting anti-allodynic effect in a spared nerve injury rat model of neuropathic pain.

Previous studies have shown an increase of insulin-like growth factor-2 (IGF2) in animal models of neuropathic pain. We aimed to examine the hypothesis that reducing the expression of IGF2 using intrathecal IGF2 small-interfering RNA (siRNA) would attenuate the development of neuropathic pain in rats after spared nerve injury (SNI). Male Wistar rats were divided into three groups: sham-operated group, in which surgery was performed to cut the muscles without injuring the nerves; SNI group, in which SNI surgery was performed to sever the nerves; and SNI + siRNA IGF2 group, in which SNI surgery was performed, and IGF2-siRNA was administered intrathecally 1 day after SNI. The rats were assessed for mechanical allodynia and cold allodynia 1 day before surgery (baseline), and at 2, 4, 6, 8, and 10 days after siRNA treatment. The rat spinal cord was collected for quantitative polymerase chain reaction and western blot analysis. Compared with the SNI group, rats that received IGF2 siRNA showed a significantly increased SNI-induced paw-withdrawal threshold to metal filament stimulation from Day 4 to Day 10 after SNI surgery. IGF2 siRNA significantly decreased the response duration from the acetone test from Day 2 to Day 10 following SNI surgery. SNI increased IGF2 mRNA expression on Day 2 and increased IGF2 protein expression on Day 8 and Day 10 in the spinal cord of the SNI rats. However, the above-mentioned effects of IGF2 mRNA and protein expression were significantly inhibited in the SNI + IGF2 siRNA group. We demonstrated that intrathecal administration of IGF2 siRNA provided significant inhibition of SNI-induced neuropathic pain via inhibition of IGF2 expression in the spinal cord. The analgesic effect lasted for 10 days. Further exploration of intrathecal IGF2 siRNA administration as a potential therapeutic strategy for neuropathic pain is warranted.

Improved potency of pyridin-2(1H)one derivatives for the treatment of mechanical allodynia.

Mechanical allodynia, a painful sensation caused by innocuous touch, is a major chronic pain symptom, which often remains without an effective treatment. There is thus a need for new anti-allodynic treatments based on new drug classes. We recently synthetized new 3,5-disubstituted pyridin-2(1H)-one derivatives. By substituting the pyridinone at the 3-position by various aryl/heteroaryl moieties and at the 5-position by a phenylamino group, we discovered that some derivatives exhibited a strong anti-allodynic potency in rats. Here, we report that varying the substitution of the pyridinone 5-position, the 3-position being substituted by an indol-4-yl moiety, further improves such anti-allodynic potency. Compared with 2, one of the two most active compounds of the first series, eleven out of nineteen newly synthetized compounds showed higher anti-allodynic potency, with two of them completely preventing mechanical allodynia. In the first series, hit compounds 1 and 2 appeared to be inhibitors of p38α MAPK, a protein kinase known to underlie pain hypersensitivity in animal models. Depending on the substitution at the 5-position, some newly synthetized compounds were also stronger p38α MAPK inhibitors. Surprisingly, though, anti-allodynic effects and p38α MAPK inhibitory potencies were not correlated, suggesting that other biological target(s) is/are involved in the analgesic activity in this series. Altogether, these results confirm that 3,5-disubstituted pyridine-2(1H)-one derivatives are of high interest for the development of new treatment of mechanical allodynia.

Ventrolateral periaqueductal gray exogenous and endogenous histamine attenuates sciatic nerve chronic constriction injury-induced neuropathic pain through opioid receptors.

The aim of the present study was to investigate the effects of intra-ventrolateral periaqueductal gray (vlPAG) microinjection of histamine and thioperamide (a histamine H3 receptor antagonist/inverse agonist) on neuropathic pain. To explore the possible mechanism, naloxone was microinjected alone or in combination with histamine and thioperamide. Neuropathic pain was induced by the left sciatic nerve chronic constriction injury. Both the right and left sides of vlPAG of the brain were surgically cannulated. Cold allodynia and mechanical hyperalgesia were recorded by acetone evaporation and von Frey filament tests. Areas under curve of allodynia and hyperalgesia were calculated. Histamine (0.50 and 2.00 µg per site), thioperamide (4.00 µg per site) and thioperamide (4.00 µg per site) before histamine (2.00 µg per site) suppressed cold allodynia and mechanical hyperalgesia after microinjection into the vlPAG. Microinjection of naloxone (0.25 and 1.00 µg per site) into the vlPAG had no effect on cold allodynia and mechanical hyperalgesia. The anti-allodynic and anti-hyperalgesic effects induced by microinjection of histamine (2.00 µg per site) and thioperamide (4.00 µg per site) into the vlPAG were inhibited by prior microinjection of naloxone (1.00 µg per site) into the same site. The above-mentioned agents did not alter locomotor activity. Based on our present results, it was concluded that exogenous (by histamine microinjection) and endogenous (by thioperamide microinjection) histamine of the vlPAG might contribute to the descending pain control mechanisms through a naloxone-sensitive mechanism.

Metformin effect in models of inflammation is associated with activation of ATP-dependent potassium channels and inhibition of tumor necrosis factor-α production

Metformin is an oral hypoglycemic drug widely used in the management of type 2 diabetes mellitus. We have recently demonstrated that metformin exhibits activity in models of nociceptive and neuropathic pain. However, little is known about its effects in experimental models of inflammation and inflammatory pain. Thus, the present study aimed to evaluate the activity of metformin in experimental models of inflammation and inflammatory pain in mice, as well as the underlying mechanisms. Previous (1h) per os (p.o.) administration of metformin (250, 500 or 1000mg/kg) inhibited the mechanical allodynia and paw edema induced by intraplantar (i.pl.) injection of carrageenan (600μg) and also the pleurisy induced by this stimulus (200μg, intrapleural). In the model of mechanical allodynia and paw edema induced by carrageenan, metformin also exhibited activity when administered after (1h) the inflammatory stimulus. Metformin (1000mg/kg) reduced the production of tumor necrosis factor-α induced by i.pl. injection of carrageenan. Metformin antiallodynic effect was not affected by previous administration of naltrexone (5 or 10mg/kg, intraperitoneal) or cyproheptadine (5 or 10mg/kg, p.o). However, this effect was abolished by previous administration of glibenclamide (20 or 40mg/kg, p.o). In conclusion, the results demonstrate the activity of metformin in models of inflammation and inflammatory pain. In addition, the results indicate that the activity of metformin may be mediated by activation of ATP-sensitive potassium channels and reduction of production of inflammatory mediators. Altogether, these results stimulate the conduction of studies aiming to evaluate whether metformin may be repositioned in the treatment of patients with painful and inflammatory disorders.

Novel Cyclic Endomorphin Analogues with Multiple Modifications and Oligoarginine Vector Exhibit Potent Antinociception with Reduced Opioid-like Side Effects.

Endomorphins (EMs) are potent pharmaceuticals for the treatment of pain. Herein, we investigated several novel EM analogues with multiple modifications and oligoarginine conjugation. Our results showed that analogues 1-6 behaved as potent μ-opioid agonists and enhanced stability and lipophilicity. Analogues 5 and 6 administered centrally and peripherally induced significant and prolonged antinociceptive effects in acute pain. Both analogues also produced long-acting antiallodynic effects against neuropathic and inflammatory pain. Furthermore, they showed a reduced acute antinociceptive tolerance. Analogue 6 decreased the extent of chronic antinociceptive tolerance, and analogue 5 exhibited no tolerance at the supraspinal level. Particularly, they displayed nontolerance-forming antinociception at the peripheral level. In addition, analogues 5 and 6 exhibited reduced or no opioid-like side effects on gastrointestinal transit, conditioned place preference (CPP), and motor impairment. The present investigation established that multiple modifications and oligoarginine-vector conjugation of EMs would be helpful in developing novel analgesics with fewer side effects.

Peripherally administered cannabinoid receptor 2 (CB2R) agonists lose anti-allodynic effects in TRPV1 knockout mice, while intrathecal administration leads to anti-allodynia and reduced GFAP, CCL2 and TRPV1 expression in the dorsal spinal cord and DRG

The transient receptor potential (TRP) superfamily of cation channels, of which the TRP vanilloid type 1 (TRPV1) receptor plays a critical role in inflammatory and neuropathic pain, is expressed on nociceptors and spinal cord dorsal horn neurons. TRPV1 is also expressed on spinal astrocytes and dorsal root ganglia (DRG) satellite cells. Agonists of the cannabinoid type 2 receptor (CB2R) suppress allodynia, with some that can bind TRPV1. The neuroimmune C–C class chemokine-2 (CCL2) expressed on injured DRG nociceptor cell bodies, Schwann cells and spinal astrocytes, stimulates immune cell accumulation in DRG and spinal cord, a known critical element in chronic allodynia. The current report examined whether two CB2R agonists, AM1710 and AM1241, previously shown to reverse light touch mechanical allodynia in rodent models of sciatic neuropathy, require TRPV1 activation that leads to receptor insensitivity resulting in reversal of allodynia. Global TRPV1 knockout (KO) mice with sciatic neuropathy given intrathecal or intraperitoneal AM1710 were examined for anti-allodynia followed by immunofluorescent microscopy analysis of lumbar spinal cord and DRG of astrocyte and CCL2 markers. Additionally, immunofluorescent analysis following intrathecal AM1710 and AM1241 in rat was performed. Data reveal that intrathecal AM1710 resulted in mouse anti-allodynia, reduced spinal astrocyte activation and CCL2 expression independent of TRPV1 gene deletion. Conversely, peripheral AM1710 in TRPV1-KO mice failed to reverse allodynia. In rat, intrathecal AM1710 and AM1241 reduced spinal and DRG TRPV1 expression, with CCL2-astrocyte and -microglial co-expression. These data support that CB2R agonists can impact spinal and DRG TRPV1 expression critical for anti-allodynia.

Blue-light treatment reduces spontaneous and evoked pain in a human experimental pain model.

Chronic pain is a frequent severe disease and often associated with anxiety, depression, insomnia, disability, and reduced quality of life. This maladaptive condition is further characterized by sensory loss, hyperalgesia, and allodynia. Blue light has been hypothesized to modulate sensory neurons and thereby influence nociception. Here, we compared the effects of blue light vs red light and thermal control on pain sensation in a human experimental pain model. Pain, hyperalgesia, and allodynia were induced in 30 healthy volunteers through high-density transcutaneous electrical stimulation. Subsequently, blue light, red light, or thermal control treatment was applied in a cross-over design. The nonvisual effects of the respective light treatments were examined using a well-established quantitative sensory testing protocol. Somatosensory parameters as well as pain intensity and quality were scored. Blue light substantially reduced spontaneous pain as assessed by numeric rating scale pain scoring. Similarly, pain quality was significantly altered as assessed by the German counterpart of the McGill Pain Questionnaire. Furthermore, blue light showed antihyperalgesic, antiallodynic, and antihypesthesic effects in contrast to red light or thermal control treatment. Blue-light phototherapy ameliorates pain intensity and quality in a human experimental pain model and reveals antihyperalgesic, antiallodynic, and antihypesthesic effects. Therefore, blue-light phototherapy may be a novel approach to treat pain in multiple conditions.

Heme oxygenase-1 in the spinal cord plays crucial roles in the analgesic effects of pregabalin and gabapentin in a spared nerve-injury mouse model

IntroductionNeuropathic pain remains one of the most intractable types of pain; although calcium channel α2δ ligands, such as pregabalin and gabapentin, are classified as first-line drugs, they have only modest efficacy. Heme oxygenase-1 (HO-1) signaling attenuates glial activation during neuropathic pain. Thus, this study aimed to investigate the effects of the blood–brain barrier (BBB)-permeable HO-1 inhibitor, tin protoporphyrin IX (SnPP), or the BBB-impermeable HO-1 inhibitor, zinc (II) protoporphyrin IX (ZnPP), on the analgesic efficacy of pregabalin and gabapentin. Additionally, we examined the effects of co-administration of SnPP with pregabalin or gabapentin on the expression of glial markers or other genes. MethodsNeuropathic pain was induced by spared nerve injury (SNI) of the sciatic nerve. The mechanical threshold was tested using the von Frey filaments. The expression of spinal glial markers or other genes was examined using reverse transcription polymerase chain reaction. ResultsSystemic HO-1 inhibition reversed the mechanical antiallodynic effects of pregabalin and gabapentin, although peripheral HO-1 inhibition did not alter the mechanical antiallodynic effects of either pregabalin or gabapentin. Intrathecal injection of SnPP or ZnPP abolished the mechanical antiallodynic effects of pregabalin and gabapentin. Pregabalin and gabapentin increased HO-1, arginase-1, and endogenous opioid precursor preproenkephalin gene expression and decreased the expression of glial markers, interleukin-1β, and inducible nitric oxide synthase. ConclusionsThis study suggests that spinal HO-1 plays a crucial role in the analgesic effects of calcium channel α2δ ligands through the attenuation of glial activation and endogenous opioid release.

Neuroprotective and anti-neuropathic actions of pulsed magnetic fields with low frequencies in rats with chronic peripheral neuropathic pain

The management of chronic peripheral neuropathic pain conditions with conventional treatments is still limited. In this present study, we aimed to determine the anti-neuropathic actions of pulsed magnetic field (PMF) treatments as a therapeutic. Effects of daily PMF treatments for 4 weeks were investigated by examining pain behaviors, hyperalgesia and allodynia, electrophysiological parameters, amplitude of compound action potential (CAP) and sciatic nerve conduction velocity (SNCV) and histopathological changes in rats with chronic constriction injury (CCI). Peripheral and central pro-inflammatory cytokines (TNF α, IL-1β and IL-17), chemokines (CCL3 and CXCL1) and angiogenic factors (VEGF and bFGF) in sciatic nerves and spinal cord tissues were also measured for determining the possible molecular action mechanisms of PMF treatment. Hyperalgesia and allodynia were observed at the first week and lasted for 4 weeks after CCI. PMF treatments caused time-dependent anti-hyperalgesic and anti-allodynic effects. PMF treatment alleviated the histopathological consequences of CCI on sciatic nerve and significantly improved the amplitude of the CAP and SNCV. PMF treatment inhibited the pro-inflammatory molecules and promoted the anti-inflammatory cytokines in neural tissues. PMF treatment also suppressed the VEGF levels and enhanced the bFGF levels in both neural tissues. The results of the present study suggested that daily PMF treatment may have neuroprotective and anti-neuropathic pain actions in rats with CCI-induced neuropathy due to its modulating effects on neuro-inflammatory and neuro-angiogenic mediators in central and peripheral neural tissues.

Key Role of Post-emptive PPAR-γ Activation in Extenuating Pain Hypersensitivity in Mononeuropathic Rats

Background: Neuropathic pain, a chronic debilitating painful condition, is frequently difficult to manage with the conventional analgesics. Emerging evidence indicates potential role of peroxisome proliferator-activated receptor (PPAR)-γ, a subfamily of nuclear receptors, in regulating inflammation and oxidative stress at transcription level. Therefore, we investigated whether activation of PPAR-γ attenuate established neuropathic pain and to delineate underlying mechanisms. Methods: Neuropathy was induced by chronic constriction injury of sciatic nerve in rats. Behavioral tests were performed to assess pain hypersensitivity and the markers of inflammation and nitroso-oxidative stress were estimated in sciatic nerve. Results: Chronic administration of pioglitazone (10 and 30 mg/kg, i.p.) for 2 weeks starting 14 days after nerve injury did not induce hypoalgesia in contralateral paws and had no effect on locomotor activity. However, pioglitazone significantly mitigated cold allodynia and thermal hyperalgesia in ipsilateral paws after nerve injury. In addition, pioglitazone reduced plasma extravasation and pro-inflammatory cytokines, TNF-α and IL-1β, following nerve injury. These effects of pioglitazone are parallel with the significant reduction in lipid peroxidation, protein carbonyls, nitrite levels as well as marked improvement in GSH and activities of SOD, catalase in injured nerves. BADGE, a PPAR-γ antagonist (30 mg/kg, i.p.) reversed the effects of pioglitazone in chronic constriction injury (CCI) rats. Conclusion: Together, the present results demonstrate that activation of PPAR-γ receptor-dependently exerted antiallodynic and antihyperalgesic effects through inhibition of inflammation and nitroso-oxidative stress in mononeuropathic rats and supporting a key role of PPAR-γ activation in extenuating existing neuropathic pain.

Participation of angiotensin-(1-7) in exercise-induced analgesia in rats with neuropathic pain

Exercise reduces neuropathic pain in animals and humans. Recent studies indicate that training exercise favors the synthesis and action of angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system (RAS), in various tissues. Interestingly, Ang-(1-7) also relieves neuropathic pain; however, it remains to be elucidated whether exercise mitigates this type of pain through Ang-(1-7). In this study, we investigated the role of Ang-(1-7) in exercise-induced analgesia in a neuropathic pain model. Male Wistar rats were ligated of lumbar spinal nerves (L5 and L6) or sham-operated. Then, they were subjected to acute (2-h) or chronic (4-week) exercise protocols. Tactile allodynia was evaluated before and after each exercise intervention. Microosmotic pumps were implanted subcutaneously for the release of Ang-(1-7) or A779 (selective Mas receptor (MasR; Ang-(1-7) receptor) antagonist). Plasma levels of Ang II and Ang-(1-7) were quantified by HPLC. Spinal nerve ligation (SNL) produced tactile allodynia. Both acute and chronic exercise reversed this neuropathic behavior. A779 treatment prevented the antiallodynic effect induced by each exercise protocol. SNL increased the plasma Ang II/Ang-(1-7) ratio; however, exercise did not modify it. Acute treatment with Ang-(1-7) via MasR mimicked exercise-mediated antinociception. Collectively, these results suggest that activation of the Ang-(1-7)/MasR axis of the RAS represents a potential novel mechanism by which exercise attenuates neuropathic pain in rats.

The Multimodal MOPr/DOPr Agonist LP2 Reduces Allodynia in Chronic Constriction Injured Rats by Rescue of TGF-β1 Signalling.

Neuropathic pain is one of the most disabling forms of chronic pain and it is characterized by hyperalgesia and allodynia linked to an aberrant processing of pain transmission and to neuroinflammation. Transforming growth factor-β1 (TGF-β1) is an anti-inflammatory cytokine, which protects against neuroinflammation. It has been demonstrated that TGF-β1 and opioid receptors signalling crosstalk results in an improvement of endogenous opioid analgesia, but it is not known whether mu opioid peptide receptor (MOPr) or delta opioid peptide receptor (DOPr) agonists can positively modulate TGF-β1 pathway. In the present study, we examined the correlation between anti-allodynic effect of LP2, a dual-target MOPr/DOPr agonist, and TGF-β1 signalling in the chronic constriction injury (CCI) model. We detected a significant decrease of active TGF-β1 and of its type II receptor TGFβ-R2 levels in the spinal cord from CCI rats and a selective deficit of TGF-β1 in microglia cells both at days 11 and 21 post-ligature, as assessed by immunofluorescence analysis. LP2, when administered from the 11 days post-ligature to 21 days, was able to reduce CCI-induced mechanical allodynia by rescue of TGF-β1 and TGFβ-R2 levels. Our data suggest that the rescue of TGF-β1 signalling by dual-target MOPr/DOPr agonist LP2 could be mediated by DOPr activation in spinal microglia, thus the dual-target approach could represent a novel pharmacological approach to increase the analgesic efficacy of MOPr agonists.

Novel Co-crystal of Pentoxifylline and Protocatechuic Acid Relieves Allodynia in Rat Models of Peripheral Neuropathic Pain and CRPS by Alleviating Local Tissue Hypoxia

Local tissue ischemic hypoxia is a peripheral process that can be targeted with topical treatment to alleviate pain under chronic pain conditions such as complex regional pain syndrome (CRPS) and peripheral neuropathic pain. We recently reported three novel salts and a co-crystal composed of vasoactive agents and antioxidant nutraceuticals, all of which produced potent topical anti-allodynic effects in the chronic postischemic pain (CPIP) rat model of CRPS. One of the products, pentx-pca, is a co-crystal synthesized from pentoxifylline (pentx) and protocatechuic acid (pca). Pentx-pca exhibited potent topical anti-allodynic effects in CPIP and rats with chronic constriction injury of the sciatic nerve exceeding effects produced individually by pentx and pca. We hypothesized that the anti-allodynic effects of pentx-pca in CPIP rats were due to its impact on local tissue oxygenation and subsequent oxygen-dependent mitochondrial respiration. Percutaneous tissue oxygen saturation (SaO2) measurements taken from the hind paw of the CPIP rats revealed that anti-allodynic doses of topical pentx-pca increased local tissue SaO2. Moreover, assessment of the oxygen-dependent mitochondrial function using a triphenyl tetrazolium chloride assay revealed that mitochondrial dysfunction significantly declined in the plantar muscle collected from CPIP rats topically treated with anti-allodynic doses of pentx-pca as compared to vehicle-treated CPIP rats. Furthermore, time-dependent resolution of plantar muscle mitochondrial dysfunction, that occurred in the CPIP rats at 6-week post procedure, paralleled the loss of the anti-allodynic response to topical treatment with pentx-pca. Our results indicated that pentx-pca produced potent anti-allodynic effects in the CPIP rat model of CRPS by alleviating peripheral tissue ischemia/hypoxia and downstream hypoxia-driven mitochondrial dysfunction.