Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain.

Methadone (Racemic methadone) exerts its antinociceptive effect by activation of mu-opioid receptors and/or blockade of NMDA receptors. The aim of this study is to determine whether the methadone analgesic effect on neuropathic pain is achieved only by the agonism of the mu-opioid receptors or cooperatively with the antagonism of the NMDA receptors. To this purpose, in rats with neuropathic pain model of chronic constriction of one sciatic nerve (CCI rats), we administered methadone before or after opioid receptor blockade with naloxone and checked its effects on the spinal Wide Dynamic Range (WDR) neuron dynamics in three experimental conditions: on the spontaneous and noxious evoked neuronal activities in control rats (sham operated and naïve); on iontophoretic NMDA induced neuronal hyperactivity in intact rats; on pain-related spontaneous and noxious evoked hyperactivities in CCI rats.

Contribution by DRt descending facilitatory pathways to maintenance of spinal neuron sensitization in rats.

We investigated in different experimental rat models the potential facilitatory contribution of the medullary dorsal reticular nucleus (DRt) descending pathway to the expressions of the sensory spinal neuron sensitization such as increased spontaneous and noxious evoked activities, responsivity to heterotopic afferences stimulation and long lasting afterdischarges (ADs). We carried out experiments by recording from ipsilateral lumbar Wide Dynamic Range (WDR) neurons and by simultaneously monitoring the DRt neuron activity in neuropathic pain rats with chronic constriction injury of one sciatic nerve (CCI), in sham-operated and in "intact" rats. In particular, we recorded the spinal neuron spontaneous activities and the activities evoked by noxious stimulations of ipsi- and contralateral sciatic supplied areas before and during DRt activity blockade.

Effects of the bisphosphonate ibandronate on hyperalgesia, substance P, and cytokine levels in a rat model of persistent inflammatory pain.

The anti-inflammatory and analgesic properties of different bisphosphonates have been demonstrated in both animal and human studies. Ibandronate is a third-generation bisphosphonate effective in managing different types of bone pain. In this study we investigated its effects in a standard pre-clinical model of inflammatory pain.

Heterotopic inputs facilitate poststimulus afterdischarges of spinal WDR neurons in rats with chronic nerve constriction.

Heterotopic inputs activate spinal wide dynamic range (WDR) neurons in rats with chronic constriction of one sciatic nerve (CCI rats). A possible contribution from these inputs, to long-lasting afterdischarges (ADs) of noxious evoked responses, was investigated during reversible input blockade from adjacent saphenous nerve and contralateral peripheral nerve territories. The results show significant AD reduction or suppression, indicating that heterotopic afferences contribute to mechanisms underlying prolonged ADs.

AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain.

An attractive alternative to the use of direct agonists at the cannabinoid receptor type 1 (CB1) in the control of neuropathic pain may be to potentiate the actions of endogenous cannabinoids. Thus, the effects of AM404, an inhibitor of anandamide uptake, were assessed in an experimental model of neuropathic pain in rats. Daily treatment with AM404 prevented, time- and dose-dependently, the development of thermal hyperalgesia and mechanical allodynia in neuropathic rats.

Contralateral input modulates the excitability of dorsal horn neurons involved in noxious signal processes. Potential role in neuronal sensitization.

Wide Dynamic Range (WDR) neurons in the spinal cord receive inputs from the contralateral side that, under normal conditions, are ineffective in generating an active response. These inputs are effective when the target WDRs change their excitability conditions. To further reveal the mechanisms supporting this effectiveness shift, we investigated the weight of the excitation of the contralateral neurons on the target WDR responses.

Efficacy of nociceptin inhibition on WDR neuron activity is enhanced in mononeuropathic rats.

Nociceptin (NC), administered microiontophoretically at different concentrations, significantly reduced the spontaneous and stimulus-evoked activity on WDR neuron in rats with chronic constriction of one sciatic nerve and showing signs of neuropathic pain. The effect was not antagonized by Naloxone. The same concentrations of NC were ineffective on the noxious stimulus evoked responses of WDR neurons in sham and intact rats.

Neuronal sensitization and its behavioral correlates in a rat model of neuropathy are prevented by a cyclic analog of orphenadrine.

N-methyl-D-aspartic acid (NMDA) is an agonist at the homonymous receptor implicated in the development of neuronal sensitization and its behavioral correlates. An effective modulation of the NMDA effects, achieved also by uncompetitive antagonists, could contribute to controlling pain symptoms in several neuropathic syndromes. Because nefopam is a known analgesic derivative of orphenadrine and of its congener diphenhydramine, both uncompetitive NMDA receptor antagonists, we tested the effect of nefopam on the developing pain and neuronal anomalies in an animal model of chronic pain with NMDA receptor involvement.

The mGluR5 selective antagonist 6-methyl-2-(phenylethynyl)-pyridine reduces the spinal neuron pain-related activity in mononeuropathic rats.

In rats with chronic constriction of one sciatic nerve (CCI rats), showing behavioural signs of neuropathic pain, 6-methyl-2-(phenylethynyl)-pyridine (MPEP), a selective mGluR5 antagonist, was intraperitoneally administered at 0.75, 1.0 and 1.

NMDA and strychnine diversely modulate spinal dorsal horn noxious responsiveness in normal rats: potential significance to sensory disorders in neuropathic pain.

Changes in neuronal excitability due to increase in excitatory transmitters and/or removal of local inhibition underlie central neuron sensitization and altered responsiveness related to painful sensory disorders. To distinguish the contribution of each of the two mechanisms, they have been mimicked separately in intact rats, by iontophoretically applying excitatory (NMDA) and disinhibitory (the glycine antagonist strychnine) substances during dorsal horn neuron recording. Wide dynamic range (WDR) neurons were extracellularly recorded at the L5-L6 lumbar level in anesthetized and paralyzed rats and an analysis was made, before and during the substance application, of the characteristics of the response to noxious stimuli applied to areas supplied by the ipsilateral sciatic nerve and the contralateral sciatic and saphenous nerves ("inappropriate" areas).

Pre-injury lidocaine treatment prevents thermal hyperalgesia and cutaneous thermal abnormalities in a rat model of peripheral neuropathy.

The effect of lidocaine pretreatment on thermal hyperalgesia and thermal skin asymmetries provoked by experimental mononeuropathy was investigated in rats. Forty anesthetized rats were given sciatic nerve ligatures according to the technique of Bennett and Xie. Rats were divided into 3 groups: 16 were ligated without lidocaine, 16 were ligated after lidocaine bathing of the nerve, and 8 were ligated after systemic lidocaine (6-8 mg/kg).

Lidocaine test in neuralgia.

Ten patients with organic nerve injury causing chronic neuropathic pain were tested for the effects of intravenous lidocaine versus saline upon psychophysical somatosensory variables. The variables assessed were the subjective magnitude of pain, area of mechanical hyperalgesia and presence and magnitude of thermal heat/cold hyperalgesia. The study methods applied to evaluate these conditions were the conventional testing of somatosensory submodalities with area mapping and the subjective magnitude estimation of spontaneous pain.

Inhibitory effect of the lateral reticular nucleus on neurons of the gigantocellularis nucleus which respond to noxious stimuli.

The effect was assessed of electrical stimulation of 'analgesic sites' in the lateral reticular nucleus (LRN) on the activity (spontaneous and evoked by noxious stimuli) of neurons in the nucleus gigantocellularis (NGC) in rabbits. The neurons (n = 145) were classified as 'nociceptive' (n = 98) and 'non-nociceptive' (n = 47) according to their responsiveness to a peripherally applied noxious heat stimulus (HS). The response to HS consisted in all cases of an increase in firing rate of up to 5 times the resting values.