The role of the endogenous neurotransmitters associated with neuropathic pain and in the opioid crisis: The innate pain-relieving system.

Neuropathic pain is a chronic pain caused by central and peripheral nerve injury, long-term diabetes or treatment with chemotherapy drugs, and it is dissimilar to other chronic pain conditions. Chronic pain usually seriously affects the quality of life, and its drug treatment may result in increased costs of social and medical care. As in the USA and Canada, in Europe, the demand for pain-relieving medicines used in chronic pain has also significantly increased, but most European countries are not experiencing an opioid crisis. In this review, the role of various endogenous transmitters (noradrenaline, dopamine, serotonin, met- and leu-enkephalins, ß-endorphin, dynorphins, cannabinoids, ATP) and various receptors (α2, µ, etc.) in the innate pain-relieving system will be discussed. Furthermore, the modulation of pain processing pathways by transmitters, focusing on neuropathic pain and the role of the sympathetic nervous system in the side effects of excessive opioid treatment, will be explained.

Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity.

In acute ischaemic brain injury and chronic neurodegeneration, the first step leading to excitotoxicity and cell death is the excessive release of Glu and the prolonged activation of Glu receptors, followed by intracellular calcium overload. There is apparent agreement that glutamatergic transmission via synaptic NMDA receptors (composed of GluN2A subunits) is neuroprotective, whereas transmission via non-synaptic NMDA receptors (composed of GluN2B subunits) is excitotoxic. Extrasynaptic NMDARs activate cell death pathways and may play a key role in Glu-induced excitotoxic neurodegeneration and apoptosis. Accordingly, the function of protective pathways may be impaired by the concomitant blockade of GluN2A-containing receptors. In contrast, the selective inhibition of non-synaptic GluN2B-containing NMDARs may be beneficial in neuroprotection because it can prevent neuronal cell death and thus maintain protective pathways.

Role of nitric oxide in modulating neurotransmitter release from rat striatum.

The effect of the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) on the basal and stimulation-evoked release of dopamine (DA) and acetylcholine (ACh) was investigated in rat striatum. The experiments were carried out in isolated superfused striatal slices, loaded with either [3H]-dopamine or [3H]-choline. We have found that L-NAME reduced the electrical field stimulation-evoked release of DA, while its enantiomer N-nitro-D-arginine methyl ester (D-NAME) was ineffective. In the presence of the nitric oxide (NO) precursor L-arginine, L-NAME failed to influence DA release. Furthermore, treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 completely reversed the effect of L-NAME on striatal DA release. In contrast, L-NAME had no effect on either the basal or the stimulation-evoked ACh release in any experimental conditions studied. Our data indicate that endogenously produced NO is involved in the modulation of striatal DA, but not in ACh release. Furthermore, it seems likely that the modulatory effect of NO is linked to activation of presynaptic NMDA receptors located on the striatal dopaminergic nerve terminals.