N-methyl-d-aspartate Receptors in the Prelimbic Cortex are Critical for the Maintenance of Neuropathic Pain

J of Neuroscience Research

Freitas

Boccella

et al. 2019

Self Cite

The chronic constriction injury (CCI) of the sciatic nerve is a nerve injury-based model of neuropathic pain (NP). Comorbidities of NP such as depression, anxiety, and cognitive deficits are associated with a functional reorganization of the medial prefrontal cortex (mPFC). Here, we have employed an adapted model of CCI by placing one single loose ligature around the sciatic nerve in mice for investigating the alterations in sensory, motor, affective, and cognitive behavior and in electrophysiological and biochemical properties in the prelimbic division (PrL) of the mPFC. Our adapted model of CCI induced mechanical allodynia, motor, and cognitive impairments and anxietyand depression-like behavior. In the PrL division of mPFC was observed an increase in GABA and a decrease in d-aspartate levels. Moreover an increase in the activity of neurons responding to mechanical stimulation with an excitation, mPFC (+), and a decrease in those responding with an inhibition, mPFC (−), was found. Altogether these findings demonstrate that a single ligature around the sciatic nerve was able to induce sensory, affective, cognitive, biochemical, and functional alterations already observed in other neuropathic pain models and it may be an appropriate and easily reproducible model for studying neuropathic pain mechanisms and treatments. K E Y W O R D Saffective and cognitive behavior, chronic constriction injury, GABA and d-aspartate levels, ongoing-and mechanically evoked neural activity, prelimbic division of the medial prefrontal cortex | 339 MEDEIROS Et al.

Section: Discussionmentioning

confidence: 99%

Characterization of the sensory, affective, cognitive, biochemical, and neuronal alterations in a modified chronic constriction injury model of neuropathic pain in mice

J of Neuroscience Research

Freitas

Boccella

et al. 2019

Self Cite

“…Supraspinal and cortical areas participate in the chronic stages of NP (14). Supporting this point of view, Medeiros et al (11) demonstrated a key role played by the rostral divisions of the frontal cortex in the elaboration of the chronic stages of NP. In fact, the prelimbic division of the medial prefrontal cortex (PrL-mPFC) is critically implicated in the chronic pain phenomenon twenty-one days after the adapted nervus ischiadicus CCI procedure to produce mechanical allodynia.…”

Section: Discussionmentioning

confidence: 90%

“…An adapted model of chronic constriction injury (CCI) of the nervus ischiadicus was used to induce NP. A single ligature consisting of a chromic catgut suture (Bioline Fios Cirúrgicos Ltda., Brazil) was loosely placed around the right nervus ischiadicus (9)(10)(11)(12). Each animal, in turn, was anesthetized with a mixture of ketamine (União Química Farmacêutica Nacional, Brazil) and xylazine (Hertape/ Calier, Brazil) (92 mg/kg and 9.2 mg/kg, respectively, ip).…”

Section: Neuropathic Pain Inductionmentioning

confidence: 99%

“…We have recently reported an improvement in this procedure in a laboratory animal model of NP, inducing CCI of the right nervus ischiadicus through a single loose ligature in an adaptation of the NP model described by Bennett and Xie in 1988 (9-11). The modified model produced sensory, affective, and cognitive disorders in rodents (9)(10)(11)(12). In addition, mechanical allodynia has been recorded twenty-one days after nervus ischiadicus CCI surgery (10,11).…”

Section: Introductionmentioning

confidence: 99%

“…The modified model produced sensory, affective, and cognitive disorders in rodents (9)(10)(11)(12). In addition, mechanical allodynia has been recorded twenty-one days after nervus ischiadicus CCI surgery (10,11).…”

Section: Introductionmentioning

confidence: 99%

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Indomethacin attenuates mechanical allodynia during the organization but not the maintenance of the peripheral neuropathic pain induced by nervus ischiadicus chronic constriction injury

Santos

et al. 2020

Braz J Med Biol Res

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The neurochemical mechanisms underlying neuropathic pain (NP) are related to peripheral and central sensitization caused by the release of inflammatory mediators in the peripheral damaged tissue and ectopic discharges from the injured nerve, leading to a hyperexcitable state of spinal dorsal horn neurons. The aim of this work was to clarify the role played by cyclooxygenase (COX) in the lesioned peripheral nerve in the development and maintenance of NP by evaluating at which moment the nonsteroidal anti-inflammatory drug indomethacin, a non-selective COX inhibitor, attenuated mechanical allodynia after placing one loose ligature around the nervus ischiadicus, an adaptation of Bennett and Xie's model in rodents. NP was induced in male Wistar rats by subjecting them to chronic constriction injury (CCI) of the nervus ischiadicus, placing one loose ligature around the peripheral nerve, and a sham surgery (without CCI) was used as control. Indomethacin (2 mg/kg) or vehicle was intraperitoneally and acutely administered in each group of rats and at different time windows (1, 2, 4, 7, 14, 21, and 28 days) after the CCI or sham surgical procedures, followed by von Frey's test for 30 min. The data showed that indomethacin decreased the mechanical allodynia threshold of rats on the first, second, and fourth days after CCI (Po0.05). These findings suggested that inflammatory mechanisms are involved in the induction of NP and that COX-1 and COX-2 are involved in the induction but not in the maintenance of NP.

Acanthoscurria gomesiana spider‐derived synthetic mygalin in the dorsal raphe nucleus modulates acute and chronic pain

J Biochem & Molecular Tox

Freitas

et al. 2021

Self Cite

Mygalin, a diacylspermidine that is naturally found in the hemolymph of the spider Acanthoscurria gomesiana, is of interest for development as a potential analgesic.Previous studies have shown that acylpolyamines modulate glutamatergic receptors with the potential to alter pain pathways. This study aimed to evaluate the effects of mygalin on acute and chronic pain in rodents. For evaluation of acute pain, Wistar rats were subjected to tail-flick and hot-plate nociceptive tests. For the evaluation of chronic neuropathic pain, a partial ligation of the sciatic nerve was performed and, 21 days later, animals were examined in hot-plate, tail-flick, acetone, and von Frey tests. Either Mygalin or vehicle was microinjected in the dorsal raphe nucleus (DRN) before the tests. Another group was pretreated with selective antagonists of glutamate receptors (LY 235959, MK-801, CNQX, and NBQX). Mygalin decreases nociceptive thresholds on both acute and chronic neuropathic pain models in all the tests performed. The lowest dose of mygalin yielded the most effective nociception, showing an increase of 63% of the nociceptive threshold of animals with neuropathic chronic pain. In conclusion, mygalin microinjection in the DRN results in antinociceptive effect in models of neuropathic pain, suggesting that acylpolyamines and their derivatives, such as this diacylspermidine, could be pursued for the treatment of neuropathic pain and development of selective analgesics.