Compelling evidence has suggested that spinal glial cells were activated by chronic morphine treatment and involved in the development of morphine tolerance. However, the mechanisms of glial activation were still largely unknown in morphine tolerance. In present study, we investigated the role of p38 mitogen-activated protein kinase (p38 MAPK) in the spinal cord in the development of chronic morphine antinociceptive tolerance. We found that intrathecal administration of morphine (15 microg) daily for 7 consecutive days significantly induced an increase in number of phospho-p38 (p-p38) immunoreactive cells in the spinal cord compared with chronic saline or acute morphine treated rats. Double immunofluorescence staining revealed that p-p38 immunoreactivity was exclusively restricted in the activated spinal microglia, not in astrocytes or neurons. Repeated intrathecal administration of 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580) (10 microg or 2 microg), a specific p38 inhibitor, 30 min before each morphine injection for 7 consecutive days significantly attenuated tolerance to morphine analgesia assessed by tail flick test. However, a single intrathecal administration of SB203580 (10 microg) did not antagonize the established tolerance to morphine analgesia. Taken together, these findings suggested that p38 MAPK activation in the spinal microglia was involved in the development of morphine antinociceptive tolerance. Inhibition of p38 MAPK by SB203580 in the spinal cord attenuated but not reversed the tolerance to morphine analgesia. The present study provides the first evidence that p38 activation in spinal microglia played an important role in the development of tolerance to morphine analgesia.
"Activated microglia are known to modify opioid function. Chronic opioids activate glia in the spinal cord and blocking microglial activation prolongs the effectiveness of morphine analgesia and prevents the development of opioid-induced hyperalgesia (Cui et al, 2006; Ferrini et al, 2013; Hutchinson et al, 2009; Raghavendra et al, 2004). Activated microglia release BDNF, which acts as a modulator of neuronal activity. "
[Show abstract][Hide abstract] ABSTRACT: Opioid dependence is accompanied by neuroplastic changes in reward circuitry leading to a negative affective state contributing to addictive behaviors and risk of relapse. The current study presents a neuroimmune mechanism through which chronic opioids disrupt ventral tegmental area (VTA) dopaminergic circuitry that contributes to impaired reward behavior. Opioid dependence was produced in rodents by treating with escalating doses of morphine. Microglial activation was observed in the VTA following spontaneous withdrawal from chronic morphine treatment. Opioid-induced microglial activation resulted in an increase in brain derived neurotrophic factor (BDNF) expression and a reduction in the expression and function of the K(+)Cl(-) co-transporter KCC2 within VTA GABAergic neurons. Inhibition of microglial activation or interfering with BDNF signaling prevented the loss of Cl(-) extrusion capacity and restored the rewarding effects of cocaine in opioid-dependent animals. Consistent with a microglial-derived BDNF-induced disruption of reward, intra-VTA injection of BDNF or a KCC2 inhibitor resulted in a loss of cocaine-induced place preference in opioid-naïve animals. The loss of the extracellular Cl(-) gradient undermines GABAA-mediated inhibition, and represents a mechanism by which chronic opioid treatments can result in blunted reward circuitry. This study directly implicates microglial-derived BDNF as a negative regulator of reward in opioid-dependent states, identifying new therapeutic targets for opiate addictive behaviors.Neuropsychopharmacology accepted article preview online, 23 July 2015. doi:10.1038/npp.2015.221.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2015; DOI:10.1038/npp.2015.221 · 7.05 Impact Factor
"The present study aims to investigate the effects of BoNT/A on the development of tolerance to a chronic morphine treatment in neuropathic mice subjected to sciatic nerve lesion, according to the Chronic Constriction Injury (CCI) model of neuropathic pain. Since it has been demonstrated that expression and activation of spinal glial cells are implicated in the development of morphine tolerance (Song and Zhao, 2001; Raghavendra et al., 2002, 2004; DeLeo et al., 2004; Watkins et al., 2005, 2009; Cui et al., 2006, 2008; Mika, 2008), we compared behavioral effects with immunofluorescence (IF) staining of the protein markers for astrocytes (glial fibrillary acidic protein; GFAP), microglia (complement receptor 3/cluster of differentiation 11b; CD11b) and neuronal nuclei (NeuN), expressed alone or colocalized with MOR and with phosphorylated p38 MAPK (p-p38), as protein marker of inflammatory process and glial cells activation in spinal cord (Watkins et al., 2001, 2009; Kim et al., 2002; Svensson et al., 2003; Hua et al., 2005). The demonstration that BoNT/A can counter the development of morphine tolerance not only in acute (Vacca et al., 2012) but also in a chronic pain condition may prove useful for the potentiality in management of pain in the clinic. "
[Show abstract][Hide abstract] ABSTRACT: The use of botulinum neurotoxin type A (BoNT/A) against pain, with emphasis for its possible use in alleviating chronic pain, still represents an outstanding challenge for experimental research. In this study, we examined the effects of BoNT/A on morphine-induced tolerance during chronic morphine treatment in neuropathic CD1 mice subjected to sciatic nerve lesion according to the Chronic Constriction Injury (CCI) model of neuropathic pain. We measured the effects of BoNT/A on CCI-induced allodynia and hyperalgesia and on the expression of glial fibrillary acidic protein (GFAP, marker of astrocytes), complement receptor 3/cluster of differentiation 11b (CD11b, marker of microglia), and neuronal nuclei (NeuN) at the spinal cord level. We also analyzed the colocalized expression of GFAP, CD11b and NeuN with phosphorylated p-38 mitogen-activated protein kinase and with μ-opioid receptor (MOR). A single intraplantar injection of BoNT/A (15pg/paw) into the injured hindpaw, the day before the beginning of chronic morphine treatment (9days of twice daily injections of 40mg/kg morphine), was able to counteract allodynia and enhancement of astrocytes expression/activation induced by CCI. In addition, BoNT/A increased the analgesic effect of morphine and countered morphine-induced tolerance during chronic morphine treatment. These effects were accompanied, in neurons, by re-expression of MORs that had been reduced by repeated morphine administration. The combinatory effects of BoNT/A and morphine could have relevant therapeutic implications for sufferers of chronic pain who could benefit of pain relief reducing tolerance due to repeated treatment with opiates.
"Numerous shared characteristics between neuropathic and sustained morphine-induced pain sensitization and analgesic tolerance led to the suggestion that these processes may share common mechanisms (Ossipov et al, 2005). Thus, similar to inflammatory and neuropathic conditions, sustained morphine treatment induced MAP kinase phosphorylation (Cui et al., 2006) elevated excitatory neuromodulator levels (Raghavendra et al., 2002) and induced a time-dependent upregulation of CB2 receptors (Lim et al., 2006) within the spinal cord of rodents. Therefore, we hypothesized that by activation of glial CB2 receptors, CB2 agonists may be able to attenuate sustained morphine-mediated spinal glial activation and thus, prevent paradoxical pain sensitization as observed in case of inflammatory and neuropathic pain states. "
[Show abstract][Hide abstract] ABSTRACT: Spinal glial activation has been implicated in sustained morphine-mediated paradoxical pain sensitization. Since activation of glial CB2 cannabinoid receptors attenuates spinal glial activation in neuropathies, we hypothesized that CB2 agonists may also attenuate sustained morphine-mediated spinal glial activation and pain sensitization. Our data indicate that co-administration of a CB2-selective agonist (AM 1241) attenuates morphine (intraperitoneal; twice daily; 6 days)-mediated thermal hyperalgesia and tactile allodynia in rats. A CB2 (AM 630) but not a CB1 (AM 251) antagonist mitigated this effect. AM 1241 co-treatment also attenuated spinal astrocyte and microglial marker and pro-inflammatory mediator (IL-1β, TNFα) immunoreactivities in morphine-treated rats, suggesting that CB2 agonists may be useful to prevent the neuroinflammatory consequences of sustained morphine treatment.
Journal of neuroimmunology 03/2012; 244(1-2):23-31. DOI:10.1016/j.jneuroim.2011.12.021 · 2.47 Impact Factor
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