Neuronal Sensitization and Its Behavioral Correlates in a Rat Model of Neuropathy Are Prevented by a Cyclic Analog of Orphenadrine

Abstract

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. A single intraperitoneal injection of nefopam was administered twenty minutes prior to the chronic constriction injury of the sciatic nerve (CCI rats). In the first 10 days, nefopam (30 mg/kg) significantly decreased behavioral signs of neuropathic pain and the stimulus-evoked electrophysiological anomalies in recordings at 14 days, with only slight manifestation afterwards. The dose of 20 mg/kg was ineffective. Nefopam injected after constriction was ineffective. In normal non-operated rats, Nefopam had no effect on the electrophysiological and behavioral parameters. Iontophoretic nefopam (1 mM, 50-80 nA, positive current) in normal rats did not change the spontaneous neuronal activity, but reduced the mean response to noxious stimuli and the concurrent iontophoretic NMDA evoked activity. In CCI rats, iontophoretic nefopam did not significantly modify the spontaneous hyperactivity but reduced significantly both the frequency of the responses to noxious stimuli, and the duration of the afterdischarge. We propose that nefopam exerts a preventive analgesic effect, with a possible role in modulating NMDA receptor-mediated effects in central sensitization.

Enhancement of Antinociception by Co-administrations of Nefopam, Morphine, and Nimesulide in a Rat Model of Neuropathic Pain

“…Moreover, many clinical studies have evaluated the analgesic efficacy of nefopam in postoperative pain [18,19]. Nefopam has shown a protective analgesic effect when used in single doses in the CCI model of chronic neuropathic pain [20]. However, as for other analgesic drugs, some unpleasant adverse effects of nefopam including dizziness, headache, nausea, vomiting, and sweating are consistent with its central mechanism of action [14,21].…”

The Effect of Nefopam Infusion during Laparascopic Cholecystectomy on Postoperative Pain

“…It inhibits 5-hydroxytriptamine and noradrenaline uptake 27, controls descending serotonergic pain 28, and interacts with dopaminergic pathways 29. In addition, nefopam has analgesic effects in a rat model of neuropathy 30 with activated NMDA receptors 31. However, while ketamine acts as an NMDA receptor antagonist to control pain, nefopam inhibits voltage-sensitive sodium channels to modulate presynaptic glutaminergic transmission 32.…”

The Potential Role of Intrathecal Nefopam in the Management of Neuropathic Pain

“…Additionally, the central nervous system is the site of action of nefopam, including the spinal cord. The findings of some studies suggest that nefopam reduces neuropathic pain by means of spinal nerve ligation at the spinal level [3,4]. Recently, the role of the 5-HT 7 (5-hydroxytryptamine 7 ) receptor has been highlighted in nociceptive modulation.…”