ABSTRACT
The present study evaluated the effects of compounds targeting extrasynaptic δ subunit-containing γ-aminobutyric acid type A receptors (δ*-GABAARs) to interrogate the role of tonic inhibition in the development of antinociceptive tolerance caused by repeated morphine administration. We investigated the effect of subchronic or acute treatment with non-steroidal positive allosteric modulators (PAMs) of δ*-GABAARs, such as 2-261, on the morphine-antinociceptive tolerance. Mice were treated twice daily with morphine for 9 days and antinociception was measured using the hot water tail immersion test. Co-treatment with 2-261 and morphine prevented morphine-antinociceptive tolerance and acute administration of 2-261 on day 9 was sufficient to reverse the tolerance. Other compounds with activity at δ*-GABAARs also reversed morphine tolerance, whereas an enaminone that lacked activity at δ*-GABAARs did not. Acute administration of 2-261 did not cause an additive or synergistic antinociceptive effect when combined with an acute submaximal dose of morphine. We then used Cre/LoxP recombination to generate GABAA δ-subunit knockout mice to corroborate the pharmacological results. Observations of male δ-knockout mice demonstrated that the δ*-GABAARs was necessary for 2-261 modulation of both analgesic tolerance and somatic withdrawal symptoms produced by subchronic morphine. While female mice still benefited from the positive effects of 2-261, the δ-subunit was not necessary for these effects, highlighting a distinction of the different pathways that could have implications for some of the sex-related differences seen in human opioid-induced outcomes. Consequently, subtype-specific allosteric modulators of GABAARs may warrant further investigation as pharmacological targets to manage tolerance and withdrawal from opioids.
Subject(s)
Analgesics, Opioid , Morphine , Analgesics/pharmacology , Analgesics, Opioid/pharmacology , Animals , Dose-Response Relationship, Drug , Female , Humans , Male , Mice , Mice, Knockout , Receptors, GABA-A , Receptors, Opioid, delta , Water , gamma-Aminobutyric AcidABSTRACT
A single threatening experience may change the behavior of an animal in a long-lasting way and elicit generalized behavioral responses to a novel threatening situation that is unrelated to the original aversive experience. Electrical stimulation (ES) of the dorsal periaqueductal gray (dPAG) produces a range of defensive reactions, characterized by freezing, escape, and post-stimulation freezing (PSF). The latter reflects the processing of ascending aversive information to prosencephalic structures, including the central nucleus of the amygdala (CeA), which allows the animal to evaluate the consequences of the aversive situation. This process is modulated by substance P (SP) and its preferred receptor, neurokinin 1 (NK1). The ventral hippocampus (VH) has been associated with the processing of aversive information and expression of emotional reactions with negative valence, but the participation of the VH in the expression of these defensive responses has not been investigated. The VH is rich in NK1 receptor expression and has a high density of SP-containing fibers. The present study examined the role of NK1 receptors in the VH in the expression of defensive responses and behavioral sensitization that were induced by dPAG-ES. Rats were implanted with an electrode in the dPAG for ES, and a cannula was implanted in the VH or CeA for injections of vehicle (phosphate-buffered saline) or the NK1 receptor antagonist spantide (100â¯pmol/0.2⯵L. Spantide reduced the duration of PSF that was evoked by dPAG-ES, without changing the aversive freezing or escape thresholds. One and 7â¯days later, exploratory behavior was evaluated in independent groups of rats in the elevated plus maze (EPM). dPAG-ES in rats that received vehicle caused higher aversion to the open arms of the EPM compared with rats that did not receive dPAG stimulation at both time intervals. Injections of spantide in the VH or CeA prevented the proaversive effects of dPAG-ES in the EPM only 1â¯day later. These findings suggest that NK1 receptors are activated in both the VH and CeA during the processing of aversive information that derives from dPAG-ES. As previously shown for the CeA, SP/NK1 receptors in the VH are recruited during PSF that is evoked by dPAG-ES, suggesting that a 24-h time window is susceptible to interventions with NK1 antagonists that block the passage of aversive information from the dPAG to higher brain areas.
Subject(s)
Avoidance Learning , Behavior, Animal , Central Amygdaloid Nucleus/drug effects , Central Nervous System Sensitization , Exploratory Behavior , Hippocampus/drug effects , Maze Learning , Neurokinin-1 Receptor Antagonists/pharmacology , Periaqueductal Gray , Receptors, Neurokinin-1/physiology , Substance P/analogs & derivatives , Animals , Avoidance Learning/drug effects , Avoidance Learning/physiology , Behavior, Animal/drug effects , Behavior, Animal/physiology , Central Nervous System Sensitization/drug effects , Central Nervous System Sensitization/physiology , Electric Stimulation , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Male , Maze Learning/drug effects , Maze Learning/physiology , Neurokinin-1 Receptor Antagonists/administration & dosage , Periaqueductal Gray/physiology , Rats , Rats, Wistar , Substance P/administration & dosage , Substance P/pharmacologyABSTRACT
BACKGROUND: The anterior pretectal nucleus (APtN) activates descending mechanisms of pain control. This study evaluated whether the APtN also controls neuropathic pain in rats. METHODS: The hypersensitivity to mechanical stimulation with an electronic von Frey apparatus and the number of Fos-immunoreactive (Fos-ir) neurons in the APtN were evaluated in rats before and after chronic constriction injury of the sciatic nerve. RESULTS: The tactile hypersensitivity was characterized by an initial phase (the 2 days following the injury) and a maintenance phase (the subsequent 7 days). The injection of 2% lidocaine (0.25 µL) or N-methyl-D-aspartate (2.5 µg/0.25 µL) into the APtN intensified the tactile hypersensitivity observed 2 days after injury but did not alter the tactile hypersensitivity observed 7 and 14 days after injury. The injection of naloxone (10 ng/0.25 µL) or methysergide (40 pg/0.25 µL) but not atropine (100 ng/0.25 µL) into the APtN also intensified the tactile hypersensitivity observed 2 days after the injury. A significant increase in the number of Fos-ir cells was found in the contralateral APtN 2 days but not 7 or 14 days after the injury. Electrical stimulation of the APtN reduced the tactile hypersensitivity at 2, 7 and 14 days after the nerve ligation. CONCLUSION: APtN exerts a tonic inhibitory influence on persistent pain. The results point out to an important role of opioid and serotonergic mediation into the APtN to inhibit hyperalgesia during the initial phase of neuropathic pain.
Subject(s)
Neural Pathways/pathology , Neuralgia/pathology , Pretectal Region/pathology , Anesthetics, Local/administration & dosage , Anesthetics, Local/pharmacology , Animals , Constriction, Pathologic/complications , Constriction, Pathologic/pathology , Hyperalgesia/physiopathology , Lidocaine/administration & dosage , Lidocaine/pharmacology , Male , Methysergide/pharmacology , N-Methylaspartate/administration & dosage , N-Methylaspartate/pharmacology , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Neurons/pathology , Pain Measurement/drug effects , Physical Stimulation , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Wistar , Sciatic Neuropathy/pathologyABSTRACT
This study reports some of the most important clinical features of the velocardiofacial syndrome (hypoplastic zygomatic arch, prominent nose with square nasal root, bilateral epicanthus, downslanting palpebral fissures, and learning disabilities) in a Brazilian boy presenting face and pinna asymmetries. These findings may facilitate the diagnosis of this syndrome.
Subject(s)
Abnormalities, Multiple , Ear, External/abnormalities , Facial Asymmetry , Facial Bones/abnormalities , Heart Defects, Congenital/complications , Learning Disabilities , Child , Humans , Male , Phenotype , SyndromeABSTRACT
This study reports some of the most important clinical features of the velocardiofacial syndrome (hypoplastic zygomatic arch, prominent nose with square nasal root, bilateral epicanthus, downslanting palpebral fissures, and learning disabilities) in a Brazilian boy presenting face and pinna asymmetries. These findings may facilitate the diagnosis of this syndrome.
Subject(s)
Humans , Male , Child , Aortic Arch Syndromes/physiopathology , Facial Asymmetry/etiology , Heart Defects, Congenital/complications , Phenotype , Heart Defects, Congenital/physiopathologyABSTRACT
EMG activity of the upper lip was measured with bipolar surface electrodes during speech and nonspeech tasks in order to assess labial function in subjects with repaired clefts. Eighteen patients between 15 and 23 years of age with repaired unilateral cleft lip (isolated or combined with repaired cleft palate) were compared to 24 matched noncleft subjects. Data analysis demonstrated that the amplitude of action potentials of the upper lip was significantly greater in the cleft group. We hypothesize that the enhanced activity of the repaired upper lip during function may contribute to the facial growth abnormalities usually seen in the cleft population.
