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Astrocytes play a key role in the maintenance of synaptic transmission by producing L-lactate via the astrocyte-neuron lactate shuttle (ANLS). Astrocyte activation in the spinal cord is involved in the expression of neuropathic pain. We investigated the role of the ANLS in the spinal cord on hyperalgesia in neuropathic pain in mice. Specific activation of dorsal horn astrocytes induced mechanical hyperalgesia, which was attenuated by α-cyano-4-hydroxycinnamate (4-CIN), an inhibitor of monocarboxylate transporters that deliver L-lactate from astrocytes to neurons. Intrathecal L-lactate administration lowered the mechanical nociceptive threshold, which was attenuated by pretreatment with 4-CIN and isosafrole (a lactate dehydrogenase inhibitor), but not gliotoxin. Intrathecal L-lactate administration significantly upregulated c-Fos and cofilin phosphorylation, which was reversed by 4-CIN. The lowered mechanical nociceptive threshold was significantly attenuated by intrathecal fluorocitrate (an astrocyte-specific Krebs cycle inhibitor), 4-CIN, and isosafrole treatment. Thus, these results suggested that, in neuropathic pain, mechanical hyperalgesia was maintained by excessive L-lactate supplied by activated astrocytes via an aberrant ANLS., (© 2018 Wiley Periodicals, Inc.)

Clinical and experimental observations indicated that 3-hydroxy-3-methylglutaryl CoA reductase inhibitor statins have pleiotropic effects. The present study determined the antinociceptive property of centrally administered simvastatin on the formalin-induced nociception in the mouse. Intrathecal administration of simvastatin at doses of 0.5 - 50 nmol dose-dependently attenuated the second, but not the first, phase of the formalin-induced nociception, which was partially reversed by mevalonate (5 µmol). Intracerebroventricular injection of simvastatin (50 nmol) did not affect the formalin-induced nociception. These results suggest that simvastatin-induced antinociception is mediated by attenuation of the sensitization of spinal nociceptive transmission.

Diabetic neuropathy is one of the most common complications in diabetes, and hyperalgesia and allodynia are serious symptoms of diabetic neuropathy. There are few therapeutic options available for the treatment of such diabetic painful neuropathy. While several reports have indicated that an abnormality of intracellular signaling molecules is involved in the pathogenesis of diabetic painful neuropathy, agents that affect these intracellular signaling molecules have failed to deliver convincing results in clinical trials. Recently, the small molecular G-protein RhoA has been shown to be involved in the pathogenesis of diabetic nephropathy. RhoA and its downstream kinase Rho kinase (ROCK) have been shown to modulate nociceptive transmission in the spinal cord. In this report, we provide a brief overview of the role of the RhoA/ROCK pathway in diabetic complications. We especially focus on the role of the spinal RhoA/ROCK pathway in the pathogenesis of diabetic painful neuropathy. Findings on the association between the spinal RhoA/ROCK pathway and diabetic painful neuropathy may lead to new strategies for its treatment., (Copyright 2010 Elsevier B.V. All rights reserved.)

Isoprenylation is crucial for the biological activation of small molecular G proteins. Activation of Rho/Rho kinase (ROCK) signaling has been reported to be involved in the initiation and maintenance of hyperalgesia caused by nerve injury and inflammation. The present study was then undertaken to examine whether the protein isoprenylation could affect thermal nociceptive threshold in the mouse spinal cord. Intrathecal administration of mevalonate (0.05-5.0 micromol) dose-dependently decreased the paw-withdrawal latencies for the thermal stimulation, indicating that mevalonate induces thermal hyperalgesia. Intrathecal pretreatment with a geranylgeranyl transferase I inhibitor GGTI-2133 (0.001-1.0 nmol) or a ROCK inhibitor Y27632 (0.001-1.0 nmol) completely blocked the mevalonate-induced thermal hyperalgesia. On the other hand, mevalonate-induced thermal hyperalgesia was only slightly attenuated by a farnesyl transferase inhibitor FTI-277 (0.01-1.0 nmol). Intrathecal injection of mevalonate increased the amount of geranylgeranylated RhoA in the spinal cord, which was completely blocked by intrathecal pretreatment with GGTI-2133. Intrathecal injection of mevalonate also produced RhoA translocation from cytosol to plasma membrane. This mevalonate-induced RhoA translocation was also blocked by intrathecal pretreatment with GGTI-2133, indicating that the RhoA translocation is triggered by RhoA geranylgeranylation. Moreover, inhibition of mevalonate synthesis by HMG-CoA reductase inhibition with simvastatin attenuated the second phase, but not the first phase, of nociceptive response to formalin. Our present results suggest that mevalonate sensitizes the spinal nociceptive transmission, which is mediated by the activation of ROCK following the RhoA geranylgeranylation.

The supraspinal and spinal antinociceptive effects of several kappa-opioid receptor agonists were examined in diabetic and non-diabetic mice using the tail-flick assay. The antinociception induced by intrathecal (i.t.), but not intracerebroventricular (i.c.v.), CI-977, a highly selective kappa(1)-opioid receptor agonist, in diabetic mice was less than that in non-diabetic mice. The antinociceptive effects of ICI-199,441 and R-84760, high potency kappa(1)-opioid receptor agonists, given i.c.v., but not i.t., were attenuated in diabetic mice compared to those in non-diabetic mice. On the other hand, the antinociceptive effects of the new kappa-opioid receptor agonist TRK-820, which has high affinity for kappa(2)- and/or kappa(3)-opioid receptors, injected both i.c.v. and i.t. in diabetic mice were markedly less than those in non-diabetic mice. These results indicate that the antinociceptive effects of those kappa-opioid receptor agonists in diabetic mice are altered in a region-specific manner in the central nervous system (CNS). The dysfunction of kappa-opioid receptor subtypes in diabetic mice may underlie this CNS region-specific variation in the effects of these kappa-opioid receptor agonists.

Beta-arrestins have been suggested to regulate mu-, delta-, and kappa-opioid receptor-mediated responses. In the present study, we examined the effects of pretreatment with beta-arrestin-2 antibody on tail-flick inhibition induced by opioid receptor agonists in the mouse spinal cord. Intrathecal (i.t.) pretreatment with beta-arrestin-2 antibody potentiated the antinociception induced by i.t.-administered mu-opioid receptor agonists [D-Ala(2),NMePhe(4),Gly-ol(5)]enkephalin (DAMGO) and endomorphin-1, but not endomorphin-2, the delta-opioid receptor agonist [D-Ala(2)]deltorphin II or the kappa-opioid receptor agonist U50,488H. The present result suggests that beta-arrestin-2 may tonically down-regulate a selected population of mu-opioid receptors activated by endomorphin-1 or DAMGO in the mouse spinal cord.

Abstract: Carnosine is a biologically active dipeptide that is found in fish and chicken muscle. Recent studies have revealed that carnosine has neuroprotective activity in zinc-induced neural cell apoptosis and ischemic stroke. In the present study, we examined the expression of carnosine in the spinal cord, and the antinociceptive potency of carnosine in a mouse model of inflammation-induced nociceptive pain. Immunohistochemical studies with antiserum against carnosine showed an abundance of carnosine-immunoreactivity in the dorsal horn of the mouse spinal cord. Double-immunostaining techniques revealed that carnosine was expressed in the neurons and astrocytes in the spinal cord. Oral administration of carnosine attenuated the number of writhing behaviors induced by the intraperitoneal administration of 0.6% acetic acid. Treatment with carnosine also attenuated the second phase, but not the first phase, of the nociceptive response to formalin. Moreover, intrathecal, but not intraplanter, administration of carnosine attenuated the second phase of the nociceptive response to formalin. Our immunohistochemical and behavioral data suggest that carnosine has antinociceptive effects toward inflammatory pain, which may be mediated by the attenuation of nociceptive sensitization in the spinal cord. [Copyright &y& Elsevier]

Abstract: Diabetic neuropathy is one of the most common complications of diabetes and causes various problems in daily life. Several investigations have noted that many factors in the spinal cord are involved in the symptoms of painful diabetic neuropathy, and there are very few effective therapeutic regimens. In the present study, we sought to elucidate the role of the RhoA/Rho kinase (ROCK) pathway in thermal hyperalgesia in diabetic mice. The intracellular localization of RhoA and the expression of eNOS were measured by western blotting. Thermal hyperalgesia was assessed by the tail-flick test and mechanical allodynia was assessed by automated von Frey filament test in streptozotocin(STZ)-induced diabetic mice. The spinal cord of STZ-treated diabetic mice showed increased membrane-bound RhoA compared to non-diabetic control. Treatment with the RhoA inhibitor exoenzyme C3, Clostridium botulinum, and the ROCK inhibitor Y27632 attenuated thermal hyperalgesia and mechanical allodynia in diabetic mice. Moreover, daily treatment with simvastatin attenuated all of those changes in diabetic mice. The expression of eNOS and NO metabolite contents in the spinal cord was decreased in diabetic mice, and these changes were normalized by treatment with simvastatin. The present results show that HMG-CoA reductase inhibitors have an inhibitory effect on thermal hyperalgesia in diabetic mice, which is mediated by an increase in NO production through the inhibition of RhoA/ROCK pathways. These results suggest that ROCK inhibitors and HMG-CoA inhibitors may be attractive compounds to relieve the symptoms of painful diabetic neuropathies. [Copyright &y& Elsevier]

Cilnidipine is a dihydropyridine derivative that inhibits N-type and L-type voltage-gated Ca 2+ channels (VDCCs). We recently reported that a selective N-type VDCC blocker attenuated the spinal long-term potentiation (LTP) of C-fiber-evoked field potentials recorded in the spinal dorsal horn of rats, which served as a model for examining synaptic function during central pain sensitization. In this study, we investigated the effects of cilnidipine on the changes related to neuropathic pain induced by nerve injury. Mechanical allodynia and hyperalgesia were evaluated by von Frey test and pin prick test, respectively. Spinal LTP of C-fiber-evoked field potentials were evaluated by in vivo electrophysiology. Intrathecally administrated cilnidipine attenuated mechanical allodynia and hyperalgesia in the spared nerve injury mouse model. Using in vivo electrophysiology in rats, cilnidipine (10 µm) administered spinally inhibited the induction and maintenance of high-frequency stimulation-induced LTP of C-fiber-evoked field potentials, while basal C-fiber-evoked field potentials in naïve rats were unaffected. The basal C-fiber-evoked field potentials in nerve-injured rats were strongly inhibited by cilnidipine. Treatment with a specific N-type VDCC blocker, ω-conotoxin GVIA, which reportedly attenuates C-fiber-evoked field potentials both before and after the induction of LTP, attenuated mechanical allodynia and hyperalgesia in nerve-injured mice. By contrast, an L-type VDCC blocker, nicardipine attenuated only mechanical hyperalgesia, but not mechanical allodynia in nerve-injured mice, and also attenuated the established LTP of C-fiber-evoked field potentials in rats. These results suggested that N-type and L-type VDCC blockers may effectively alleviate the hyperalgesia and allodynia associated with neuropathic pain without affecting normal pain perception. [ABSTRACT FROM AUTHOR]