n-n--dibenzhydrylethane-1-2-diamine-dihydrochloride and Neuralgia

Paclitaxel-induced acute pain syndrome (P-APS), characterized by deep muscle aches and arthralgia, occurs in more than 70% of patients who receive paclitaxel. P-APS can be debilitating for patients and lead to reductions and discontinuation of potentially curable therapy. Despite being relatively common in clinical practice, no clear treatment exists for P-APS and the underlying mechanisms remain poorly defined. Regulation of glutamatergic transmission by metabotropic glutamate receptors (mGluRs) has received growing attention with respect to its role in neuropathic pain. To our knowledge, no study has been conducted on alterations and functions of group III mGluR7 signaling in P-APS.. In the present study, we determined whether a single administration of paclitaxel induces glutamatergic alterations and whether mGluR7 activation blocks paclitaxel-induced neuropathic pain by suppressing glial reactivity in the spinal cord.. A single paclitaxel injection dose-dependently induced acute mechanical and thermal hypersensitivity, and was associated with increased glutamate level accompanied by reduction in mGluR7 expression in the spinal cord. Selective activation of mGluR7 by its positive allosteric modulator, AMN082, blocked the development of paclitaxel-induced acute mechanical and thermal hypersensitivity, without affecting the normal pain behavior of control rats. Moreover, activation of mGluR7 by AMN082 inhibited glial reactivity and decreased pro-inflammatory cytokine release during P-APS. Abortion of spinal glial reaction to paclitaxel alleviated paclitaxel-induced acute mechanical and thermal hypersensitivity.. There results support the hypothesis that spinal mGluR7 signaling plays an important role in P-APS; Selective activation of mGluR7 by its positive allosteric modulator, AMN082, blocks P-APS in part by reducing spinal glial reactivity and neuroinflammatory process.

Topics: Acute Pain; Allosteric Regulation; Animals; Benzhydryl Compounds; Excitatory Amino Acid Agonists; Glutamic Acid; Male; Neuralgia; Paclitaxel; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Spinal Cord

The study investigated the role of the metabotropic glutamate receptor subtype 7 (mGluR7) in pain signalling in the dorsal striatum of sham and neuropathic rats. Supraspinal circuitries involved in the dorsal striatum control of pain were also explored. In the sham rats, microinjection of N,N'-bis(diphenylmethyl)-1,2-ethanediamine (AMN082), a selective mGluR7 positive allosteric modulator, into the dorsal striatum, facilitated pain, increased the activity of the ON cells and inhibited the activity of the OFF cells in the rostral ventromedial medulla, and decreased glutamate levels in the dorsal striatum. Conversely, AMN082 inhibited pain and the activity of the ON cells while increased the activity of the OFF cells in rats with spared nerve injury (SNI) of the sciatic nerve. AMN082 also decreased glutamate levels in the dorsal striatum of SNI rats. The effect of AMN082 on mechanical allodynia and glutamate release was blocked by 6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydro-4(5H)-benzoxazolone (ADX71743), a selective mGluR7 negative allosteric modulator. Moreover, in the sham rats, AMN082 increased the activity of total nociceptive convergent neurons in the dorsal reticular nucleus while in the SNI rats, such activity was decreased. The administration of lidocaine into the subthalamic nucleus abolished the effect of AMN082 on the total nociceptive convergent neurons in the sham rats but not in the SNI rats. Thus, the dual effect of mGluR7 in facilitating or inhibiting pain responses may be due to the recruitment of different pathways of the basal ganglia, the indirect or direct pathway, in physiological or pathological conditions, respectively.

Topics: Animals; Benzhydryl Compounds; Benzoxazoles; Corpus Striatum; Glutamic Acid; Hyperalgesia; Lidocaine; Male; Medulla Oblongata; Microinjections; Neuralgia; Neurons; Neuroprotective Agents; Pain; Rats; Receptors, Metabotropic Glutamate; Reticular Formation; Sciatic Nerve; Subthalamic Nucleus

Metabotropic glutamate could contribute to the development of neuropathic pain-related behaviors. Previously, we have confirmed that the glutamic acid and dizocilpine maleate in the hippocampal CA3 region are involved in the modulation of noxious stimulation. However, whether the metabotropic glutamate receptor 7 (mGluR7) can modulate the pain-evoked electrical activities of pain-excited neurons and pain-inhibited neurons in the hippocampal CA3 region is not clear.. The study aimed to examine the effects of mGluR7 allosteric agonist N,N'-dibenzhydrylethane- 1,2-diamine dihydrochloride (AMN082) and antagonist 6-(4-methoxyphenyl)-5-methyl-3- pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP) on the pain-evoked electrical activities of pain-excited neurons and pain-inhibited neurons in the CA3 region of rats.. A train of electric impulses applied to the sciatic nerve were used for noxious stimulation. The bio-electrical activities of pain-excited neuron or pain-inhibited neuron in the CA3 region were recorded by a glass microelectrode.. Our results exhibited that intra-CA3 region administration of the glutamic acid or AMN082 increased the pain-evoked discharged frequency and shortened the latency of pain-excited neuron, while decreased the pain-evoked discharged frequency and prolonged the inhibitory duration of paininhibited neuron in the CA3 region. The intra-CA3 region microinjection of MMPIP produced the opposite response.. These findings demonstrated that the glutamic acid and mGluR7 in hippocampal CA3 region are involved in the modulation of nociceptive information transmission by regulating pain-evoked electric activities of pain-excited neurons and pain-inhibited neurons.

Topics: Analgesics, Non-Narcotic; Animals; Benzhydryl Compounds; CA3 Region, Hippocampal; Excitatory Amino Acid Agents; Glutamic Acid; Male; Microelectrodes; Neuralgia; Neurons; Nociceptive Pain; Pyridones; Rats, Wistar; Receptors, Metabotropic Glutamate; Sciatic Nerve; Synaptic Transmission