Substance P (SP), a putative nociceptive transmitter, is increased in the CSF of patients with fibromyalgia syndrome (FMS). Because excitatory amino acids (EAAs) also appear to transmit pain, we hypothesized that CSF EAAs may be similarly involved in this syndrome. We found that the mean concentrations of most amino acids in the CSF did not differ amongst groups of subjects with primary FMS (PFMS), fibromyalgia associated with other conditions (SFMS), other painful conditions not exhibiting fibromyalgia (OTHER) or age-matched, healthy normal controls (HNC). However, in SFMS patients, individual measures of pain intensity, determined using an examination-based measure of pain intensity, the tender point index (TPI), covaried with their respective concentrations of glutamine and asparagine, metabolites of glutamate and aspartate, respectively. This suggests that re-uptake and biotransformation mask pain-related increases in EAAs. Individual concentrations of glycine and taurine also correlated with their respective TPI values in patients with PFMS. While taurine is affected by a variety of excitatory manipulations, glycine is an inhibitory transmitter as well as a positive modulator of the N-methyl-D-asparate (NMDA) receptor. In both PFMS and SFMS patients, TPI covaried with arginine, the precursor to nitric oxide (NO), whose concentrations, in turn, correlated with those of citrulline, a byproduct of NO synthesis. These events predict involvement of NO, a potent signaling molecule thought to be involved in pain processing. Together these metabolic changes that covary with the intensity of pain in patients with FMS may reflect increased EAA release and a positive modulation of NMDA receptors by glycine, perhaps resulting in enhanced synthesis of NO.
"Genetic variants resulting in decreased COMT activity have been associated with chronic pain conditions such as fibromyalgia  and TMD , which are linked to increased levels of catecholamines   and production of proinflammatory molecules   . Specifically, patients with fibromyalgia   and TMD     show higher levels of NO derivatives (eg, nitrite and nitrate) and cytokines such as TNFa, IL-1b, IL-6, and CCL2. "
[Show abstract][Hide abstract] ABSTRACT: Decreased activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, contributes to pain in humans and animals. Previously, we demonstrated that development of COMT-dependent pain is mediated by both β2-and β3-adrenergic receptors (β2-and β3ARs). Here, we investigated molecules downstream of β2-and β3ARs driving pain in animals with decreased COMT activity. Based on evidence linking their role in pain and synthesis downstream of β2-and β3ARstimulation, we hypothesized that nitric oxide (NO) and pro-inflammatory cytokines drive COMT-dependent pain. To test this, we measured plasma NO derivatives and cytokines in rats receiving the COMT inhibitor OR486 in the presence or absence of the β2AR antagonist ICI118,551+β3AR antagonist SR59230A. We also assessed if the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) and cytokine neutralizing antibodies block the development of COMT-dependent pain. Results showed that animals receiving OR486 exhibited higher levels of NO derivatives, tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2) in a β2-and β3AR-dependent manner. Additionally, inhibition of NO synthases and neutralization of the innate immunity cytokines TNFα, IL-1β, and IL-6 blocked the development of COMT-dependent pain. Finally, we found that NO influences TNFα, IL-1β, IL-6 and CCL2levels, while TNFα and IL-6 influence NO levels. Altogether, these results demonstrate that β2-and β3ARs contribute to COMT-dependent pain, at least partly, by increasing NO and cytokines. Furthermore, they identify β2-and β3ARs, NO, and pro-inflammatory cytokines as potential therapeutic targets for pain patients with abnormalities in COMT physiology.
"These results are consistent with those of previous in vitro and in vivo studies showing that chronic pain elevates glutamate release in the mPFC   . Similarly, an increased glutamate level in the cerebrospinal fluid has been found in patients with persistent pain  . Pathological pain-induced central sensitization involves enhanced presynaptic glutamate release and requires increased postsynaptic receptor-mediated responses  . "
[Show abstract][Hide abstract] ABSTRACT: Although nerve injury-induced long-term postsynaptic changes have been investigated, less is known regarding the molecular mechanisms within presynaptic axonal terminals. We investigated the molecular changes in presynaptic nerve terminals underlying chronic pain-induced plastic changes in the medial prefrontal cortex (mPFC). After neuropathic pain was induced by a spared nerve injury (SNI) in rats, we assessed the release of excitatory neurotransmitter glutamate by using in vitro synaptosomal preparation from the mPFC. We also measured the levels of synaptic proteins and protein kinases in synaptosomes by using Western blot. The results showed that unilateral long-term SNI augmented depolarization-evoked glutamate release from synaptosomes of the bilateral mPFC. This result was confirmed by a rapid destaining rate of FM1-43 dye in SNI-operated rats. Unilateral long-term nerve injury also significantly increased synaptic proteins (including synaptophysin, synaptotagmin, synaptobrevin, syntaxin, and SNAP-25) in synaptosomal fractions from the bilateral mPFC, and ultrastructure images demonstrated increased synaptic vesicular profiles in synaptosomes from SNI animals. Chronic pain upregulated the phosphorylation of endogenous protein kinases, including extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Ca(2+)/calmodulin-dependent kinase II (CaMKII), and synapsin I, the primary presynaptic target of ERK1/2 and CaMKII. Both presynaptic proteins and protein kinases were upregulated after SNI in a time-dependent manner. These results indicate that the long-term neuropathic pain-induced enhancement of glutamate release in the mPFC is linked to increased synaptic vesicle proteins and the activation of the ERK1/2- and CaMKII-synapsin signaling cascade in presynaptic axonal terminals.
"conditions involve increased plasma and cerebrospinal fluid substance P (SP) concentrations (Larson et al., 2000). There are studies which showed that SP is co-localised with serotonin, norepinephrine and dopamine within the same neuron in the mammalian central nervous system (Chan-Palay et al., 1978; Hahn and Bannon, 1998; Hokfelt et al., 1987; Pelletier et al., 1981). "
[Show abstract][Hide abstract] ABSTRACT: Pain and depression are frequent co-morbid disorders. The prevalence rate of depression is several times higher in patients with chronic pain than in the general population but the mechanism underlying this association is unknown. A combination of interactions between neurotransmitters, neuropeptides, oxidative and nitrosative stress and cytokines are thought to take part in pathogenesis of pain as well as depression. Thus, the aim of the present study was two-fold, first to investigate the interplay between nociception and associated depression and second to investigate the protective potential of berberine against the reserpine-induced nociceptive and depressive behaviour and further to explore the role of oxidative-nitrosative stress mediated inflammatory cascade and apoptotic signalling pathway in this dyad.
Nociception and associated depression were induced by administration of reserpine (1mg/kg subcutaneous daily) for three consecutive days. This behavioural deficit was integrated with decrease in the biogenic amine (dopamine, norepinephrine and serotonin) levels along with increased substance P concentration, oxidative-nitrosative stress, inflammatory cytokines, NF-κβ and caspase-3 levels in different brain regions (cortex and hippocampus) of the reserpinised rats.
More studies are still warranted in similar rodent models of pain and depression, so, that the present findings can be further substantiated to establish the clinical effectiveness of berberine in a subset of patients suffering from pain as well as depression.
The findings from the current study suggested that reserpine-induced neurochemical alterations and dysregulation of oxidative-nitrosative stress induced inflammatory cascade underlies the co-morbidity of nociceptive behaviour and associated depression in rats.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.