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Positive allosteric modulators of nonbenzodiazepine γ-aminobutyric acidA receptor subtypes for the treatment of chronic pain
- Source :
- Pain, vol 160, iss 1
- Publication Year :
- 2019
- Publisher :
- eScholarship, University of California, 2019.
-
Abstract
- Chronic neuropathic pain may be caused, in part, by loss of inhibition in spinal pain processing pathways due to attenuation of local GABAergic tone. Nociception and nocifensive behaviors are reduced after enhancement of tonically activated extrasynaptic GABA(A)R mediated currents by agonist ligands for δ subunit-containing GABA(A)Rs. However, typical ligands that target δ subunit-containing GABA(A)Rs are limited due to sedative effects at higher doses. We used the spinal nerve ligation (SNL) and gp120 models of experimental neuropathic pain to evaluate compound 2–261, a non-benzodiazepine (BZ) site positive allosteric modulator (PAM) of α(4)β(3)δ GABA(A)Rs optimized to be non-sedative by selective activation of β(2/3) subunit-containing GABA(A)Rs over receptor subtypes incorporating β(1) subunits. Similar levels of 2–261 were detected in the brain and plasma following intraperitoneal administration. While systemic 2–261 did not alter sensory thresholds in sham-operated animals, it significantly reversed SNL-induced thermal and tactile hypersensitivity in a GABA(A)R dependent fashion. Intrathecal 2–261 produced conditioned place preference (CPP) and elevated dopamine levels in the nucleus accumbens of nerve-injured, but not sham-operated rats. Additionally, systemic pretreatment with 2–261 blocked CPP from spinal clonidine in SNL rats. Moreover, 2–261 reversed thermal hyperalgesia and partially reversed tactile allodynia in the gp120 model of HIV-related neuropathic pain. The effects of 2–261 likely required interaction with the α(4)β(3)δ GABA(A)R since 2–301, a close structural analog of 2–261 with limited extrasynaptic receptor efficacy, was not active. Thus, 2–261 may produce pain relief with diminished side-effects through selective modulation of β(2/3) subunit-containing extrasynaptic GABA(A)Rs.
- Subjects :
- Male
Patch-Clamp Techniques
Nonbenzodiazepine
Messenger
HIV Infections
GABA(A) receptors
Pharmacology
Neurodegenerative
Neuropathic pain
Positive allosteric modulation
Medical and Health Sciences
Nucleus Accumbens
Rats, Sprague-Dawley
GABA
0302 clinical medicine
030202 anesthesiology
Peripheral Nerve Injuries
Dopamine release
Anesthesiology
Receptors
2.1 Biological and endogenous factors
Aetiology
Pain Measurement
GABAA receptor
Chemistry
Pain Research
Chronic pain
Conditioned place preference
Nociception
Neurology
Hyperalgesia
Neurological
Drug
Chronic Pain
beta(2/3) subunits
Agonist
Pain Threshold
Allosteric modulator
medicine.drug_class
Article
Dose-Response Relationship
03 medical and health sciences
Operant
Receptors, GABA
Allosteric Regulation
Behavioral and Social Science
medicine
Animals
RNA, Messenger
GABA Modulators
Peripheral Neuropathy
Dose-Response Relationship, Drug
Animal
Psychology and Cognitive Sciences
Neurosciences
medicine.disease
Rats
Disease Models, Animal
Anesthesiology and Pain Medicine
Disease Models
Physical Endurance
Conditioning, Operant
RNA
Neurology (clinical)
Sprague-Dawley
030217 neurology & neurosurgery
Conditioning
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Pain, vol 160, iss 1
- Accession number :
- edsair.doi.dedup.....0880e0be16f4ebda5ad6174bfd207fef