The Role of Spinal Dopaminergic Transmission in the Analgesic Effect of Nefopam on Rat Inflammatory Pain

Abstract

BackgroundNefopam has been known as an inhibitor of the reuptake of monoamines, and the noradrenergic and/or serotonergic system has been focused on as a mechanism of its analgesic action. Here we investigated the role of the spinal dopaminergic neurotransmission in the antinociceptive effect of nefopam administered intravenously or intrathecally.MethodsThe effects of intravenously and intrathecally administered nefopam were examined using the rat formalin test. Then we performed a microdialysis study to confirm the change of extracellular dopamine concentration in the spinal dorsal horn by nefopam. To determine whether the changes of dopamine level are associated with the nefopam analgesia, its mechanism was investigated pharmacologically via pretreatment with sulpiride, a dopaminergic D2 receptor antagonist.ResultsWhen nefopam was administered intravenously the flinching responses in phase I of the formalin test were decreased, but not those in phase II of the formalin test were decreased. Intrathecally injected nefopam reduced the flinching responses in both phases of the formalin test in a dose dependent manner. Microdialysis study revealed a significant increase of the level of dopamine in the spinal cord by intrathecally administered nefopam (about 3.8 fold the baseline value) but not by that administered intravenously. The analgesic effects of intrathecally injected nefopam were not affected by pretreatment with sulpiride, and neither were those of the intravenous nefopam.ConclusionsBoth the intravenously and intrathecally administered nefopam effectively relieved inflammatory pain in rats. Nefopam may act as an inhibitor of dopamine reuptake when delivered into the spinal cord. However, the analgesic mechanism of nefopam may not involve the dopaminergic transmission at the spinal level.

Improvement of Pain Management by Nefopam in a Rat Adjuvant-Induced Arthritis Model

“…Furthermore, in animals with high inflammation at the zenith of clinical scores (at D13), nefopam slightly reduced the pain score. Nefopam has been shown to have antinociceptive effects on rodents ( 8 , 9 ), so its administration should decrease arthritis-induced pain perceived by animals and may also lead to a higher level of mobility. A previous study has demonstrated a correlation between nefopam administration and improvement of motor coordination ( 11 ).…”

“…Nefopam is an antinociceptive compound, part of benzoxazocine class drugs, which acts centrally at spinal and supra-spinal sites ( 8 ). Therefore, it acts through different mechanisms of action compared to NSAID or opioids ( 9 ). Even though its mechanism of action is not fully understood, nefopam seems to be involved in the inhibition of reuptake of monoamines (norepinephrine, serotonin, and dopamine) in the central nervous system.…”

<p>The Antiallodynic Effect of Nefopam on Vincristine-Induced Neuropathy in Mice</p>

“…27 Several studies have demonstrated the anti-nociceptive effects of nefopam using a variety of routes of administration and for various indications. [9][10][11][28][29][30] Nefopam reduced thermal hypersensitivity after acute and postoperative pain in rats. 31 Intraperitoneal nefopam showed an antiallodynic effect mediated by adenosine triphosphate-sensitive potassium channel in rats with spinal nerve ligation-induced neuropathy.…”

Effects of nefopam on catheter-related bladder discomfort in patients undergoing ureteroscopic litholapaxy

“…Unlike the serotonin, which mainly affects the CNS, analgesic pathway mediated by nefopam-induced activation of the dopamine receptors, has not been elucidated. However, according to animal study, dopaminergic analgesic pathway by nefopam is not observed at the spinal level and may be possible at the supraspinal level [ 26 ].…”