Robert P. Bonin

The Prevention of Chronic Postsurgical Pain Using Gabapentin and Pregabalin: A Combined Systematic Review and Meta-Analysis

BACKGROUND:Many clinical trials have demonstrated the effectiveness of gabapentin and pregabalin administration in the perioperative period as an adjunct to reduce acute postoperative pain. However, very few clinical trials have examined the use of gabapentin and pregabalin for the prevention of chronic postsurgical pain (CPSP). We (1) systematically reviewed the published literature pertaining to the prevention of CPSP (≥2 months after surgery) after perioperative administration of gabapentin and pregabalin and (2) performed a meta-analysis using studies that report sufficient data. A search of electronic databases (Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, IPA, and CINAHL) for relevant English-language trials to June 2011 was conducted. METHODS:The following inclusion criteria for identified clinical trials were used for entry into the present systematic review: randomization; double-blind assessments of pain and analgesic use; report of pain using a reliable and valid measure; report of analgesic consumption; and an absence of design flaws, methodological problems or confounders that render interpretation of the results ambiguous. Trials that did not fit the definition of preventive analgesia and did not assess chronic pain at 2 or more months after surgery were excluded. RESULTS:The database search yielded 474 citations. Eleven studies met the inclusion criteria. Of the 11 trials, 8 studied gabapentin, 4 of which (i.e., 50%) found that perioperative administration of gabapentin decreased the incidence of chronic pain more than 2 months after surgery. The 3 trials that used pregabalin demonstrated a significant reduction in the incidence of CPSP, and 2 of the 3 trials also found an improvement in postsurgical patient function. Eight studies were included in a meta-analysis, 6 of the gabapentin trials demonstrated a moderate-to-large reduction in the development of CPSP (pooled odds ratio [OR] 0.52; 95% confidence interval [CI], 0.27 to 0.98; P = 0.04), and the 2 pregabalin trials found a very large reduction in the development of CPSP (pooled OR 0.09; 95% CI, 0.02 to 0.79; P = 0.007). CONCLUSIONS:The present review supports the view that perioperative administration of gabapentin and pregabalin are effective in reducing the incidence of CPSP. Better-designed and appropriately powered clinical trials are needed to confirm these early findings.

Chloride extrusion enhancers as novel therapeutics for neurological diseases

The K+-Cl− cotransporter KCC2 is responsible for maintaining low Cl− concentration in neurons of the central nervous system (CNS), which is essential for postsynaptic inhibition through GABAA and glycine receptors. Although no CNS disorders have been associated with KCC2 mutations, loss of activity of this transporter has emerged as a key mechanism underlying several neurological and psychiatric disorders, including epilepsy, motor spasticity, stress, anxiety, schizophrenia, morphine-induced hyperalgesia and chronic pain. Recent reports indicate that enhancing KCC2 activity may be the favored therapeutic strategy to restore inhibition and normal function in pathological conditions involving impaired Cl− transport. We designed an assay for high-throughput screening that led to the identification of KCC2 activators that reduce intracellular chloride concentration ([Cl−]i). Optimization of a first-in-class arylmethylidine family of compounds resulted in a KCC2-selective analog (CLP257) that lowers [Cl−]i. CLP257 restored impaired Cl− transport in neurons with diminished KCC2 activity. The compound rescued KCC2 plasma membrane expression, renormalized stimulus-evoked responses in spinal nociceptive pathways sensitized after nerve injury and alleviated hypersensitivity in a rat model of neuropathic pain. Oral efficacy for analgesia equivalent to that of pregabalin but without motor impairment was achievable with a CLP257 prodrug. These results validate KCC2 as a druggable target for CNS diseases.

GABAA receptor subtypes underlying general anesthesia

General anesthetics produce a constellation of behavioral responses and widespread neurodepression. Recent studies have implicated the gamma-aminobutyric acid (GABA) subtype A receptor as a primary anesthetic target. During the past decade, considerable progress has been made in dissecting the behavioral effects of anesthetics according to the subunit composition of GABA(A) receptors. In this review, we describe how particular GABA(A) receptor subtypes expressed in different brain regions are critical for the expression of behavioral endpoints, such as amnesia, sedation, and hypnosis.

Pharmacological enhancement of δ-subunit-containing GABAA receptors that generate a tonic inhibitory conductance in spinal neurons attenuates acute nociception in mice

&NA; The development of new strategies for the treatment of acute pain requires the identification of novel nonopioid receptor targets. This study explored whether δ‐subunit‐containing GABAARs (δGABAARs) in neurons of the spinal cord dorsal horn generate a tonic inhibitory conductance in vitro and whether δGABAAR activity regulates acute nociception. Whole‐cell recordings revealed that δGABAARs generate a tonic inhibitory conductance in cultured spinal neurons and lamina II neurons in spinal cord slices. Increasing δGABAAR function by applying the δGABAAR‐preferring agonist 4,5,6,7‐tetrahydroisoxazolo [5,4‐c]pyridine‐3‐ol (THIP) increased the tonic current and inhibited neuronal excitability in spinal neurons from wild‐type (WT) but not δ subunit null‐mutant (Gabrd−/−) mice. In behavioral studies, baseline δGABAAR activity did not regulate acute nociception; however, THIP administered intraperitoneally or intrathecally attenuated acute nociception in WT but not Gabrd−/− mice. In the formalin nociception assay, the phase 1 response was similar for WT and Gabrd−/− mice. In contrast, the phase 2 response, which models central sensitization, was greater in Gabrd−/− mice than WT. THIP administered intraperitoneally or intrathecally inhibited phase 1 responses of WT but not Gabrd−/− mice and had no effect on phase 2 responses of WT mice. Surprisingly, THIP reduced the enhanced phase 2 response in Gabrd−/− mice. Together, these results suggest that δGABAARs in spinal neurons play a major physiological and pharmacological role in the regulation of acute nociception and central sensitization. Spinal δ‐subunit‐containing GABAA receptors were identified with electrophysiological methods and behavioral models as novel targets for the treatment of acute pain.

A simplified up-down method (SUDO) for measuring mechanical nociception in rodents using von Frey filaments

BackgroundThe measurement of mechanosensitivity is a key method for the study of pain in animal models. This is often accomplished with the use of von Frey filaments in an up-down testing paradigm. The up-down method described by Chaplan et al. (J Neurosci Methods 53:55–63, 1994) for mechanosensitivity testing in rodents remains one of the most widely used methods for measuring pain in animals. However, this method results in animals receiving a varying number of stimuli, which may lead to animals in different groups receiving different testing experiences that influences their later responses. To standardize the measurement of mechanosensitivity we developed a simplified up-down method (SUDO) for estimating paw withdrawal threshold (PWT) with von Frey filaments that uses a constant number of five stimuli per test. We further refined the PWT calculation to allow the estimation of PWT directly from the behavioral response to the fifth stimulus, omitting the need for look-up tables.ResultsThe PWT estimates derived using SUDO strongly correlated (r > 0.96) with the PWT estimates determined with the conventional up-down method of Chaplan et al., and this correlation remained very strong across different levels of tester experience, different experimental conditions, and in tests from both mice and rats. The two testing methods also produced similar PWT estimates in prospective behavioral tests of mice at baseline and after induction of hyperalgesia by intraplantar capsaicin or complete Freund’s adjuvant.ConclusionSUDO thus offers an accurate, fast and user-friendly replacement for the widely used up-down method of Chaplan et al.

A spinal analog of memory reconsolidation enables reversal of hyperalgesia

Hyperalgesia arising from sensitization of pain relays in the spinal dorsal horn shares many mechanistic and phenotypic parallels with memory formation. We discovered that mechanical hyperalgesia could be rendered labile and reversible in mice after reactivation of spinal pain pathways in a process analogous to memory reconsolidation. These findings reveal a previously unknown regulatory mechanism underlying hyperalgesia and demonstrate the existence of reconsolidation-like processes in a sensory system.

Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents

Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide (10panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia.

Hypothalamic CRH neurons orchestrate complex behaviours after stress

All organisms possess innate behavioural and physiological programmes that ensure survival. In order to have maximum adaptive benefit, these programmes must be sufficiently flexible to account for changes in the environment. Here we show that hypothalamic CRH neurons orchestrate an environmentally flexible repertoire of behaviours that emerge after acute stress in mice. Optical silencing of CRH neurons disrupts the organization of individual behaviours after acute stress. These behavioural patterns shift according to the environment after stress, but this environmental sensitivity is blunted by activation of PVN CRH neurons. These findings provide evidence that PVN CRH cells are part of a previously unexplored circuit that matches precise behavioural patterns to environmental context following stress. Overactivity in this network in the absence of stress may contribute to environmental ambivalence, resulting in context-inappropriate behavioural strategies.

Reconsolidation and the regulation of plasticity: moving beyond memory

Memory reconsolidation is a protein synthesis-dependent process that preserves, in some form, memories that have been destabilized through recall. Reconsolidation is a nearly universal phenomenon, occurring in a diverse array of species and learning tasks. The function of reconsolidation remains unclear but it has been proposed as a mechanism for updating or strengthening memories. Observations of an analog of reconsolidation in vitro and in sensory systems indicate that reconsolidation is unlikely to be a learning-specific phenomenon and may serve a broader function. We propose that reconsolidation arises from the activity-dependent induction of two coincident but opposing processes: the depotentiation and repotentiation of strengthened synapses. These processes suggest that reconsolidation reflects a fundamental mechanism that regulates and preserves synaptic strength.

The physiological properties and therapeutic potential of α5-GABAA receptors

The notion that drug treatments can improve memory performance has moved from the realm of science fiction to that of serious investigation. A popular working hypothesis is that cognition can be improved by altering the balance between excitatory and inhibitory neurotransmission. This review focuses on the unique physiological and pharmacological properties of GABA(A)Rs [GABA (gamma-aminobutyric acid) subtype A receptors] that contain the alpha(5) subunit (alpha(5)-GABA(A)R), as these receptors serve as candidate targets for memory-enhancing drugs.