Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission.

The integration of somatosensory information is generally assumed to be a function of the central nervous system (CNS). Here we describe fully functional GABAergic communication within rodent peripheral sensory ganglia and show that it can modulate transmission of pain-related signals from the peripheral sensory nerves to the CNS. We found that sensory neurons express major proteins necessary for GABA synthesis and release and that sensory neurons released GABA in response to depolarization. In vivo focal infusion of GABA or GABA reuptake inhibitor to sensory ganglia dramatically reduced acute peripherally induced nociception and alleviated neuropathic and inflammatory pain. In addition, focal application of GABA receptor antagonists to sensory ganglia triggered or exacerbated peripherally induced nociception. We also demonstrated that chemogenetic or optogenetic depolarization of GABAergic dorsal root ganglion neurons in vivo reduced acute and chronic peripherally induced nociception. Mechanistically, GABA depolarized the majority of sensory neuron somata, yet produced a net inhibitory effect on the nociceptive transmission due to the filtering effect at nociceptive fiber T-junctions. Our findings indicate that peripheral somatosensory ganglia represent a hitherto underappreciated site of somatosensory signal integration and offer a potential target for therapeutic intervention.

Chronic tiagabine administration and aggressive responding in individuals with a history of substance abuse and antisocial behavior.

Anticonvulsants, notably those which modulate GABA activity, have shown efficacy in reducing aggressive behavior. Previously, we found dose-related decreases in human aggressive responding following acute tiagabine administration. Here, we examined the effects of chronic tiagabine over a 5-week period. Twelve individuals at increased risk for aggressive and violent behavior (currently on parole/probation with personality and/or substance use disorders) were randomly assigned to placebo (n = 6) or an escalating dose sequence of placebo, 4 mg, 8 mg, 12 mg, placebo (n = 6). Data were analyzed using both frequentist and Bayesian mixed models, evaluating aggressive behavior as a function of time, dose condition, and their interaction. For aggressive responding, there was a significant interaction of drug condition and time. Aggression in the tiagabine condition decreased for each additional week in the study, while participants in the placebo condition failed to demonstrate similar change over time. For monetary-reinforced responding, no drug or drug by time interactions were observed, suggesting specificity of drug effects on aggression. The small number of subjects limits the generality of the findings, and previous studies with tiagabine are limited to acute dosing and case report investigations. However, the present data provide an indication that tiagabine merits further examination as an agent for management of impulsive aggression.

An open pilot study of tiagabine in alcohol dependence: tolerability and clinical effects.

There is evidence that GABAergic anticonvulsants can be efficacious in the treatment of alcohol dependence and in the prevention of alcohol relapse because these agents act on the substrate that is involved in alcoholism. Tiagabine, a selective GABA transporter1 reuptake inhibitor, may be a promising candidate for the treatment of alcohol-dependent individuals. In this randomized, open pilot study, we aimed to investigate the efficacy and tolerability of tiagabine as adjunctive treatment of alcohol-dependent individuals (N = 60) during the immediate post-detoxification period and during a 6-month follow-up period following alcohol withdrawal. A control non-medicated group of alcohol-dependent individuals (N = 60) was used for comparisons in terms of anxiety and depressive symptoms, craving and drinking outcome. Although a steady improvement in terms of psychopathology, craving and global functioning was observed in both groups throughout the study, subjects on tiagabine improved significantly more compared to the control subjects (P < 0.001). Furthermore, the relapse rate in the tiagabine group was lower than in the control group (7 vs 14.3%). Tiagabine was well tolerated and only a minority of the participants reported some adverse effects in the beginning of tiagabine treatment. Results from this study suggest that tiagabine is a safe and effective medication for the management of alcohol dependence when given adjunctively to a standard psychotherapy treatment. Further studies are warranted before definite conclusions can be reached.