The Role of GABA in the Mediation and Perception of Pain

Enna, S.J.; McCarson, Kenneth E.

doi:10.1016/s1054-3589(06)54001-3

Cited by 240 publications

(163 citation statements)

References 118 publications

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“…However, the moderate skin picking behavior in this subject was rather puzzling. Given the postulated role of GABA in the mediation and perception of pain, 27 we would have anticipated that sparing the GABA A receptor subunit gene clusters would have lessened this behavior. In addition, he manifested the common behavioral characteristics of individuals with PWS including temper tantrums, easily angered and rigidness.…”

Section: Discussionmentioning

confidence: 99%

“…MS-MLPA reliably detected the deletion as evidenced by 100% agreement with our laboratory data and aCGH. It also provided more detailed information regarding the size of the deletion than standard FISH due to many (25)(26)(27)(28)(29)(30)(31)(32) probes across the 15q11.2-q13 region. Thus, the MS-MLPA technique allows for a reasonable approximation of the BPs and deletion size.…”

Section: Discussionmentioning

confidence: 99%

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Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes

et al. 2011

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Prader-Willi syndrome (PWS) is a multisystem, contiguous gene disorder caused by an absence of paternally expressed genes within the 15q11.2-q13 region via one of the three main genetic mechanisms: deletion of the paternally inherited 15q11.2-q13 region, maternal uniparental disomy and imprinting defect. The deletion class is typically subdivided into Type 1 and Type 2 based on their proximal breakpoints (BP1-BP3 and BP2-BP3, respectively). Despite PWS being a well-characterized genetic disorder the role of the specific genes contributing to various aspects of the phenotype are not well understood. Methylationspecific multiplex ligation-dependent probe amplification (MS-MLPA) is a recently developed technique that detects copy number changes and aberrant DNA methylation. In this study, we initially applied MS-MLPA to elucidate the deletion subtypes of 88 subjects. In our cohort, 32 had a Type 1 and 49 had a Type 2 deletion. The remaining seven subjects had unique or atypical deletions that were either smaller (n¼5) or larger (n¼2) than typically described and were further characterized by array-based comparative genome hybridization. In two subjects both the PWS region (15q11.2) and the newly described 15q13.3 microdeletion syndrome region were deleted. The subjects with a unique or an atypical deletion revealed distinct phenotypic features. In conclusion, unique or atypical deletions were found in B8% of the deletion subjects with PWS in our cohort. These novel deletions provide further insight into the potential role of several of the genes within the 15q11.2 and the 15q13.3 regions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes

et al. 2011

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“…Similarly, several neurosteroids such as allopregnanolone will bind to the GABA-A ionophore and force conformational changes enhancing GABA effects [235,236]. Immunohistochemical studies have shown dense staining in spinal Rexed laminae for several alpha, beta and gamma subunits likely corresponding to primary afferents [237,238] presumably localized on primary afferent terminals. Electrophysiological studies have indeed shown GABA-A receptors to be present on both large and small afferents [239] and such studies have emphasized the potent regulation by benzodiazepines of the excitability of small, nociceptive, primary afferents through their associated GABA-A receptors [240].…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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“…GABA A receptors have been widely reported to be involved in several models of somatic pain and are actively pursued as potential targets for novel analgesic drugs. [28][29][30] In contrast, their role in visceral pain condition was confirmed only recently. Sengupta et al 31 reported that down regulation of microRNA-mediated GABA A1 receptor subunit in adult spinal cord following neonatal cystitis was responsible for the development of chronic visceral pain in rats.…”

Section: Gamma Aminobutyric Acid Receptorsmentioning

confidence: 99%

Role of Principal Ionotropic and Metabotropic Receptors in Visceral Pain

Kannampalli

Sengupta

2015

J Neurogastroenterol Motil

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Visceral pain is the most common form of pain caused by varied diseases and a major reason for patients to seek medical consultation. It also leads to a significant economic burden due to workdays lost and reduced productivity. Further, long-term use of non-specific medications is also associated with side effects affecting the quality of life. Despite years of extensive research and the availability of several therapeutic options, management of patients with chronic visceral pain is often inadequate, resulting in frustration for both patients and physicians. This is, most likely, because the mechanisms associated with chronic visceral pain are different from those of acute pain. Accumulating evidence from years of research implicates several receptors and ion channels in the induction and maintenance of central and peripheral sensitization during chronic pain states. Understanding the specific role of these receptors will facilitate to capitalize on their unique properties to augment the therapeutic efficacy while at the same time minimizing unwanted side effects. The aim of this review is to provide a concise review of the recent literature that reports on the role of principal ionotropic receptors and metabotropic receptors in the modulation visceral pain. We also include an overview of the possibility of these receptors as potential new targets for the treatment of chronic visceral pain conditions. (J Neurogastroenterol Motil 2015;21:147-158)

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The Role of GABA in the Mediation and Perception of Pain

Cited by 240 publications

References 118 publications

Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes

Unique and atypical deletions in Prader–Willi syndrome reveal distinct phenotypes

Current and Future Issues in the development of spinal agents for the management of pain

Role of Principal Ionotropic and Metabotropic Receptors in Visceral Pain

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