THE EFFECT OF COBALT CHLORIDE PRECONDITIONING ON PACLITAXEL-INDUCED PERIPHERAL NEUROPATHY.

INTRODUCTION: Recent studies indicate that Cobalt Chloride (CoC12) modulates mitochondrial activity. There is emerging data suggesting that Paclitaxel-induced peripheral neuropathy (PIPN) is a consequence of the drug's mitochondrial toxicity. AIM: to assess the effect of CoC12 preconditioning on PIPN in an animal model. MATERIAL AND METHOD: PIPN was induced by 7 daily consecutive i.p. Paclitaxel (PXT) administrations. Male BALB/c mice were divided into three groups as follows: group A--CoC12 (12.5 mg/kg b.w.) for three weeks (preconditioning) followed by I week of PXT, group B--saline for three weeks, followed by 1 week of PXT and group C--saline for four weeks. Thermal and mechanical allodynia were assessed by means of paw withdrawal latency (PWL). RESULTS: In group A, CoC12 preconditioning lead to a decrease in both thermal and mechanical PWLs. 7 days after the last dose of PXT, however, values returned to normal in group A and allodynia for both thermal and mechanical stimuli was noted in group B (p < 0.05). CONCLUSIONS: CoC12 preconditioning seems to protect against PIPN. Although CoC12 administration decreased thermal and mechanical PWLs, subsequent P administration did not lead to the persistent mechanical and thermal allodynia that was noted in the P-alone group. Further studies are required for determining the exact relationship between CoC12 and PIPN.

THE EFFECTS OF RIBOFLAVIN AND METHYLENE BLUE ON NOCICEPTION AND VISCERAL PAIN.

BACKGROUND: Methylene Blue (MB) can prevent electron leaking, increase mitochondrial oxidative phosphorylation, and reduce ROS overproduction under pathological conditions, currently being trace evidence that it can alter pain perception in humans by local administration during certain surgical procedures. Riboflavin or vitamin B2 (B2) constitutes a part of the vitamin B group, which in recent studies shows a growing implication in the treatment of some pathology that imply pain management. AIM: To investigate the effect of one dose of Riboflavin and Methylene Blue on nociception and visceral pain in mice. METHODS: A total of 48 BALB/c male mice were divided into 3 groups: MB Group, B2 Group and C Group. MB (5 mg/kg b.w.), B2 (100 mg/kg b.w.) or an equivalent volume of saline was administered intraperitoneally. Mice were tested before (baseline) and after drugs administration over a 4h period. Nociception was evaluated by means of Hot Plate Test (HPT) and TFT (Tail Flick Test). Visceral pain was evaluated 2h after administration. RESULTS: Four hours after MB administration we recorded an analgesic effect on the hot plate test (p < 0.05 at 30, 60 and 240 min). No significant effect on the TFT was noticed. B2 vitamin had an antinociceptive effect as compared to control group only for HPT that persisted for 2h but had no effect on TFT. Both MB and B2 vitamin have shown an analgesic effect (p < 0.01) on visceral pain when compared to the control group but the pain inhibition was more important after riboflavin administration. CONCLUSIONS: Even if the exact mechanisms are not clarified by our study, we demonstrated that both ATP modulators (MB & B2 vitamin) have analgesic effect on visceral pain and nociception.

Preconditioning with cobalt chloride modifies pain perception in mice.

Cobalt chloride (CoCl2) modifies mitochondrial permeability and has a hypoxic-mimetic effect; thus, the compound induces tolerance to ischemia and increases resistance to a number of injury types. The aim of the present study was to investigate the effects of CoCl2 hypoxic preconditioning for three weeks on thermonociception, somatic and visceral inflammatory pain, locomotor activity and coordination in mice. A significant pronociceptive effect was observed in the hot plate and tail flick tests after one and two weeks of CoCl2 administration, respectively (P<0.001). Thermal hyperalgesia (Plantar test) was present in the first week, but recovered by the end of the experiment. Contrary to the hyperalgesic effect on thermonociception, CoCl2 hypoxic preconditioning decreased the time spent grooming the affected area in the second phase of the formalin test on the orofacial and paw models. The first phase of formalin-induced pain and the writhing test were not affected by CoCl2 preconditioning. Thus, the present study demonstrated that CoCl2 preconditioning has a dual effect on pain, and these effects should be taken into account along with the better-known neuro-, cardio- and renoprotective effects of CoCl2.

Pain modulation by curcumin and ascorbic acid in mice.

AIM: The present study aims to evaluate whether ascorbic acid (AA) and curcumin, two substances with redox properties, have similar effects on different models of pain in mice. MATERIALS AND METHODS: This study included a total of 28 mice that were divided into four groups. One group (AA) received intraperitoneally 500 mg/kg b.w. AA for 21 days and the 2-nd group (curcumin) received 120 mg/kg b.w. curcumin by gastric gavage for two weeks. Other two groups serve as control and received vehicle in a dose--time manner similar to that of the treated groups. The pain models (oro-facial formalin induced pain, paw formalin induced pain and visceral pain) were performed 24 h after the last dose. RESULTS: When compared with control groups, curcumin significantly decreases pain perception in oro-facial (p = 0.01 1-st phase, p = 0.002 2-nd phase) and paw formalin induced pain (p = 0.04 1-st and 2-nd phase) while AA stimulates pain perception in acid acetic induced visceral pain (p = 0.05) and increases oro-facial inflammatory pain induced by formalin ( p = 0.02) but demonstrates analgesic effects on paw formalin induced pain (p = 0.003 1-st phase, p = 0.01 2-nd phase). CONCLUSIONS: ROS production is important in pain modulation. Structures involved in the process of pain have different antioxidant defense capacities. Curcumin and AA are able to modulate pain perception, but beside their antioxidant capacities, there are other mechanisms involved.

In vitro and in vivo pharmacological profile of the 5-benzyl analogue of 14-methoxymetopon, a novel mu opioid analgesic with reduced propensity to alter motor function.

Opioids are the most effective analgesics for pain management, and efficient pain control is a therapeutic priority. Herein, we describe the synthesis and pharmacological activities of the 5-benzyl analogue of the mu opioid analgesic 14-methoxymetopon (14-MM). The result of the replacement of the 5-methyl in 14-MM with a benzyl group on in vitro opioid receptor binding and functional profiles, and in vivo behavioural properties, i.e. nociception and motor activity, was investigated. In rodent brain membranes, the 5-benzyl derivative showed high affinity at the micro opioid receptor and decreased interaction with delta and kappa receptors, hence displaying a similar binding profile as 14-MM. It displayed potent agonist activity in vitro and in vivo. In in vitro guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTPgammaS) binding assay, it activated G-proteins in rat brain membranes through a micro opioid receptor-mediated mechanism having significantly enhanced potency compared to DAMGO (D-Ala(2),Me-Phe(4),Gly-ol(5)]enkephalin), and to the micro opioid agonist morphinans 14-MM, 14-O-methyloxymorphone (14-OMO) and morphine. In vivo, the 5-benzyl analogue of 14-MM elicited dose-dependent and naloxone-sensitive antinociceptive effects in hot-plate and tail-flick tests in mice after subcutaneous (s.c.) administration. Its analgesic potency was comparable to 14-MM, and was 50-fold higher than that of morphine. Contrary to morphine, 14-MM and 14-OMO, no motor dysfunction was produced by the new opioid in the mouse rotarod test at any of the tested doses. In summary, the 5-benzyl analogue of 14-MM emerged as a novel potent mu opioid antinociceptive agent with reduced propensity to cause unwanted motor impairment.

Lack of estrogen increases pain in the trigeminal formalin model: a behavioural and immunocytochemical study of transgenic ArKO mice.

In order to examine the effect of estrogen on facial pain, we first compared the face-rubbing evoked by a formalin injection in the lip of aromatase-knockout (ArKO) mice, lacking endogenous estrogen production, 17 beta-estradiol-treated ArKO mice (ArKO-E2) and wild-type (WT) littermates. During the 'acute' phase of pain the time spent rubbing was similar in the three groups, whereas during the following 'interphase' and the second phase of pain, grooming was increased in ArKO mice. Estradiol-treatment restored a behaviour similar to WT group. To better understand estrogens modulation on pain processes, we examined changes in 5-HT and CGRP innervations of trigeminal nucleus caudalis (TNC) in ArKO, ArKO-E2 and WT groups sacrificed during the interphase. Whereas serotonin and CGRP immunoreactivities were comparable in WT and ArKO non-injected control groups, our data showed that 9 min after formalin injection, the density of serotoninergic terminals increased significantly in WT, but not in ArKO mice, while that of CGRP-immunoreactive fibers was lower in WT than in ArKO mice on the injected side. Estradiol-treatment only partially reversed these changes in ArKO-E2 mice. We conclude that estrogen deprivation in ArKO mice can be responsible for increased nociceptive response and that it is accompanied by transmitter changes favouring pro- over anti-nociceptive mechanisms in TNC during interphase of the formalin model. That estradiol-treatment completely reverses the behavioural abnormality suggests that estrogens absence produces chiefly functional activation-dependent changes. However, the fact that the immunohistochemical abnormalities were not totally normalized by estradiol-treatment suggested that some permanent developmental alterations may occur in ArKO mice.

Motor cortex plasticity--from physiology to clinical neurology.

Neurophysiologic, neuroanatomic and neuroimaging studies conducted over the past two decades reveal that the cerebral cortex is functionally and structurally dynamic. The functional topography of the motor cortex can be modified by a variety of experimental manipulations, including peripheral or central injury, electrical stimulation, pharmocologic treatment or behavioral experience. Recent evidence demonstrates that functional alterations in motor cortex organization are accompanied by changes in dendritic and synaptic structure, as well as alterations in the regulation of cortical neurotransmitter systems. This article describes the state of the science regarding the main mechanisms implicated in the motor cortex plasticity, the main tools used for its investigation and the consequence of the recent discoveries on the therapeutic and rehabilitation procedures for the brain-injured persons.