Effects of Adjuvant Analgesics on Cerebral Ischemia-Induced Mechanical Allodynia

Abstract

Central post-stroke pain (CPSP), a potential sequela of stroke, is classified as neuropathic pain. Although we recently established a CPSP-like model in mice, the effects of adjuvant analgesics as therapeutic drugs for neuropathic pain in this model are unknown. Hence, the aim of the present study was to assess the usefulness of our model by evaluating the effects of adjuvant analgesics used for treating neuropathic pain in this mouse model of CPSP. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). The development of hind paw mechanical allodynia was measured after BCAO using the von Frey test. The mechanical allodynia was significantly increased on day 3 after BCAO compared with that during the pre-BCAO assessment. BCAO-induced mechanical allodynia was significantly decreased by intraperitoneal injections of imipramine (a tricyclic antidepressant), mexiletine (an antiarrhythmic), gabapentin (an antiepileptic), or a subcutaneous injection of morphine (an opioid receptor agonist) compared with that following vehicle treatment in BCAO-mice. By contrast, milnacipran (a serotonin and norepinephrine reuptake inhibitor), paroxetine (selective serotonin reuptake inhibitor), carbamazepine (antiepileptic), and indomethacin (nonsteroidal anti-inflammatory drug) did not affect the BCAO-induced mechanical allodynia. Our results show that BCAO in mice may be useful as an animal model of CPSP. In addition, BCAO-induced mechanical allodynia may be suppressed by some adjuvant analgesics used to treat neuropathic pain.Key words central post-stroke pain; global ischemia; allodynia; neuropathic pain Pain may occur with actual substantial or even potential histologic lesions, producing uncomfortable sensory and emotional experiences, according to the definition by the International Association for the Study of Pain. One type of pain, neuropathic pain, is caused by dysfunctional peripheral or central nerves and results in the appearance of allodynia and hypersensitivity to pain.1,2) Cerebral stroke patients may experience several types of pain, including musculoskeletal pain, headache, and neuropathic central post-stroke pain (CPSP).Among the different types of neuropathic pain, CPSP is an especially intractable condition to treat. CPSP is associated with various symptoms, such as burning and lancinating pain, and the incidence of CPSP after cerebral stroke is reportedly 1-14%. 3,4) In clinical studies, the risk factors associated with CPSP are the degree of brain infarction, sexual dimorphism, alcohol intake, depression anamnesis, statin use, dyslipidemia, diabetes, and peripheral vascular disorder.5) The pathogenic mechanisms for CPSP and neuropathic pain appear similar at the point of excitation of primary afferent fibers and for epistatic or central excitation or suppression pathway disorders. Recently, we established a CPSP-like animal model by experimentally inducing focal (middle cerebral artery occlusion model) or global cerebral ischemia (bilateral carotid artery occlusion model; BCAO). 6,...

Cerebral Ischemia Changed the Effect of Metabosensitive Muscle Afferents on Somatic Reflex Without Affecting Thalamic Activity

“…To our knowledge, no previous study measured mechanical sensibility to pressure with EVF test after 2 h of MCAO. These observations were in contradiction with previous works in which a reduced mechanical threshold to pressure was observed after global brain ischemia or focal ischemia of the thalamus, reflecting tactile hypersensibility and/or allodynia in neuropathic pain models ( Matsuura et al, 2016a , b ). Contrary to ART, the EVF test did not reveal mechanical sensibility disorders of the right forepaw.…”

No evidence of potentiation of buprenorphine by milnacipran in healthy subjects using a nociceptive test battery

“…Furthermore, it has been shown that milnacipran reduces thermal and mechanical allodynia in a rat model of neuropathic pain (chronic constriction injury of the sciatic nerve) (Berrocoso et al, 2011). However, in another model of neuropathic pain in mice (central post-stroke pain model), milnacipran did not affect mechanical allodynia thresholds (Matsuura et al, 2016). Co-administration of milnacipran with tramadol potentiated the antihyperalgesic effect of tramadol (Onal et al, 2007), which used chronic constriction injury model as a model for neuropathic pain.…”

Revisión comparativa de dolor central post-ictus y otras causas de origen encefálico: fisiopatología y tratamiento

“…Indometacina no demostró tener un efecto analgésico como coadyuvante en un modelo murino de DCPI 45 . No hay estudios que demuestren su efectividad en humanos.…”

“…Los antiinflamatorios no esteroideos (AINES) no han demostrado efectividad para aliviar el dolor neuropático; de hecho, hay pocos ensayos clínicos que comprueben su eficacia 43,44 . En el caso de DCPI, un estudio en un modelo animal de DCPI demostró que la indometacina no era útil para disminuir la alodinia causada por una oclusión carotídea bilateral, sugiriendo su ineficacia para el tratamiento en DCPI 45 .…”