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1.
Pain ; 163(7): 1414-1423, 2022 07 01.
Article in English | MEDLINE | ID: mdl-34724682

ABSTRACT

ABSTRACT: Diabetic neuropathy, often associated with diabetes mellitus, is a painful condition with no known effective treatment except glycemic control. Studies with neuropathic pain models report alterations in cannabinoid and opioid receptor expression levels; receptors whose activation induces analgesia. We examined whether interactions between CB1R and opioid receptors could be targeted for the treatment of diabetic neuropathy. For this, we generated antibodies that selectively recognize native CB1R-MOR and CB1R-DOR heteromers using a subtractive immunization strategy. We assessed the levels of CB1R, MOR, DOR, and interacting complexes using a model of streptozotocin-induced diabetic neuropathy and detected increased levels of CB1R, MOR, DOR, and CB1R-MOR complexes compared with those in controls. An examination of G-protein signaling revealed that activity induced by the MOR, but not the DOR agonist, was potentiated by low nanomolar doses of CB1R ligands, including antagonists, suggesting an allosteric modulation of MOR signaling by CB1R ligands within CB1R-MOR complexes. Because the peptide endocannabinoid, hemopressin, caused a significant potentiation of MOR activity, we examined its effect on mechanical allodynia and found that it blocked allodynia in wild-type mice and mice with diabetic neuropathy lacking DOR (but have CB1R-MOR complexes). However, hemopressin does not alter the levels of CB1R-MOR complexes in diabetic mice lacking DOR but increases the levels of CB1R-DOR complexes in diabetic mice lacking MOR. Together, these results suggest the involvement of CB1R-MOR and CB1R-DOR complexes in diabetic neuropathy and that hemopressin could be developed as a potential therapeutic for the treatment of this painful condition.


Subject(s)
Cannabinoids , Diabetes Mellitus, Experimental , Diabetic Neuropathies , Neuralgia , Animals , Diabetes Mellitus, Experimental/complications , Diabetic Neuropathies/drug therapy , Disease Models, Animal , Hyperalgesia/drug therapy , Hyperalgesia/etiology , Ligands , Mice , Neuralgia/drug therapy , Receptors, Opioid , Receptors, Opioid, mu/metabolism
2.
Behav Brain Res ; 250: 211-21, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-23692698

ABSTRACT

Motor cortex stimulation (MCS) is used as a therapy for patients with refractory neuropathic pain. Experimental evidence suggests that the motor cortex (MC) is involved in the modulation of normal nociceptive response, but the underlying mechanisms have not been clarified yet. In previous studies, we demonstrated that MCS increases the nociceptive threshold of naive conscious rats by inhibiting thalamic sensory neurons and disinhibiting the neurons in periaqueductal gray (PAG), with the involvement of the opioid system. The aim of this study was to investigate the possible somatotopy of the motor cortex on MCS-induced antinociception and the pattern of neuronal activation evaluated by Fos and Egr-1 immunolabel in an attempt to better understand the relation between MC and analgesia. Rats received epidural electrode implants placed over the MC, in three distinct areas (forelimb, hindlimb or tail), according to a functional mapping established in previous studies. Nociceptive threshold was evaluated under 15-min electrical stimulating sessions. MCS induced selective antinociception in the limb related to the stimulated cortex, with no changes in other evaluated areas. MCS decreased Fos immunoreactivity (Fos-IR) in the superficial layers of the dorsal horn of the spinal cord for all evaluated groups and increased Fos-IR in the PAG, although no changes were observed in the PAG for the tail group. Egr-1 results were similar to those obtained for Fos. Data shown herein demonstrate that MCS elicits a substantial and selective antinociceptive effect, which is mediated, at least in part, by the activation of descendent inhibitory pain pathway.


Subject(s)
Electric Stimulation/methods , Hyperalgesia/therapy , Motor Cortex/physiology , Pain Threshold/physiology , Analysis of Variance , Animals , Disease Models, Animal , Early Growth Response Protein 1/metabolism , Electrodes , Extremities/innervation , Forelimb/physiopathology , Functional Laterality , Gene Expression Regulation/physiology , Male , Nociceptors/physiology , Oncogene Proteins v-fos/metabolism , Pain Measurement , Periaqueductal Gray/metabolism , Physical Stimulation/adverse effects , Rats , Rats, Wistar , Single-Blind Method , Spinal Cord/metabolism , Spinal Cord/pathology , Time Factors
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