Gabapentin increases expression of subunit-containing GABAA receptors
Gabapentin (also known as Neurontin) is clinically prescribed for the treatment of seizures, pain, and anxiety. While gabapentin is known to modulate voltage-gated calcium channels, some studies have suggested the effects of gabapentin are also dependent on GABAergic inhibition. However, gabapentin neither binds GABA receptors nor increases GABA release, thus its precise mechanisms of action remain unclear and is what UTCSP scientists, Dr. Beverly Orser, Dr. Robert Bonin, and collaborators, aimed to uncover.
To determine whether GABA receptors are involved in gabapentin’s action the authors started by measuring levels of the GABAA receptor, as changes in cell surface expression of ion channels is a key way to modulating neuronal activity. In this study, they found that gabapentin treatment increased surface expression of the δ subunit of GABAA receptor in the cerebellum and hippocampus. The δ subunit is typically expressed outside of synapses and accordingly, neurons from mice pretreated with gabapentin displayed increased tonic GABAA receptor-dependent inhibitory currents.
They next sought to test whether the GABAA receptor δ subunit was required for known behavioural effects of gabapentin, such as ataxia, anxiolysis, and analgesia, by conducting behaviour assays with mice lacking GABAA receptor δ subunit expression (Gabrd-/-). Unlike wild type mice that exhibit reduced motor coordination (tested with Rotarod) and reduced anxiety behaviour (tested with elevated plus maze) following gabapentin administration, Gabrd-/- mice given gabapentin showed no change in these behaviours. However, gabapentin remained effective in reducing pain behaviour after formalin injection in Gabrd-/- mice, similar to wild type mice.
Together, these results suggest that the ataxic and anxiolytic effects of gabapentin are dependent on the δ subunit of GABAA receptors, but its analgesic properties are δ subunit-independent. Since diminished GABAA receptor δ subunit expression is observed in certain psychiatric disorders, such as depression, gabapentin’s ability to upregulate δ subunit expression may serve as a potential novel therapeutic for such conditions.
These results suggest that the ataxic and anxiolytic effects of gabapentin are dependent on the δ subunit of GABAA receptors, but its analgesic properties are δ subunit-independent.
Conditioned pain modulation is not unidirectional: both hyper- and hypoalgesia can arise depending on the stimulus
Conditioned pain modulation (CPM) is the phenomenon in which one painful stimulus (the conditioning stimulus) affects the pain perception of a second stimulus (the test stimulus) at a different site.
Hypoalgesic CPM, in which the conditioning stimulus reduces pain response to the test stimulus, is known as diffuse noxious inhibitory control (DNIC), or simply put – “pain inhibits pain”. However, numerous human studies have found highly variable and contradictory results to DNIC, where some observe hypoalgesia after conditioned stimulus and others show hyperalgesia. To understand the variability of CPM response a team led by Dr. Jeffrey Mogil, in collaboration with UTCSP scientist Dr. Loren Martin, used rodent models to systematically test the effects of CPM using multiple conditioning and test stimuli.
Using CD-1 mice given acetic acid as the conditioning stimulus, they observed hyperalgesia in response to thermal and mechanical test stimuli, contradicting DNIC. This controversial observation was reproduced in DBA/2J mice and Sprague-Dawley rats, and also using a different conditioning stimulus – orofacial formalin. They next showed that increasing the intensity of the conditioning stimulus (i.e., increased acetic acid concentration) only exacerbated the hyperalgesic response to the test stimuli.
Nonetheless, hypoalgesic CPM (or DNIC) was observed under some scenarios: mice given a highly noxious test stimulus were more tolerant. For example, while acetic acid injection in mice increased their sensitivity to 46oC (low-intensity thermal stimulus), it reduced their sensitivity to 52oC (high-intensity). Hypoalgesia from CPM was also observed after peripheral nerve injury, where neuropathic mice showed higher tolerance to mechanical test stimuli after receiving an acetic acid conditioning stimulus.
The results of this study suggest that the effects of CPM are dependent on test stimulus intensity and can be bidirectional, resulting in either a hyperalgesic or hypoalgesic effect. This paper also demonstrates that fully understanding a phenomenon requires studying it under varying conditions.
The results of this study suggest that the effects of CPM are dependent on test stimulus intensity and can be bidirectional, resulting in either a hyperalgesic or hypoalgesic effect. This paper also demonstrates that fully understanding a phenomenon requires studying it under varying conditions.