Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • Although GABA C receptors were

    2022-06-24

    Although, GABA-C receptors were originally described in the spinal cord [16], clues to their physiological function arise mainly from studies in the visual system [5], [26]. In mammals, GABA-C receptors are found abundantly in cone photoreceptors and bipolar cell axon terminals, where they participate in GABAergic feed-back inhibition from horizontal cells and amacrine cells, respectively [21], [25]. Perhaps due to a region-specific differential expression of these receptors, GABA elicits mixed GABA-A and GABA-C receptor currents in bipolar cells [10], [38]. The slower kinetics of GABA-C receptors when coupled to fast, transient actions of GABA-A receptors, helps maintain the fidelity in visual information processing, by allowing precise controls over spatio-temporal filtering of synaptic input into the retinal ganglionic cells [6], [38]. In the CA1 region of the hippocampus, they have been shown to block the paired-pulse depression of GABA-A receptor mediated inhibitory postsynaptic currents [43]. Exogenous introduction of the GABA-C receptors into cultured hippocampal neurons have been shown to suppress glutamate-induced hyperexcitability and delay neuronal cell death [4]. The flexibility that GABA-C receptors impart to synaptic inhibition, independently or via synergistic interactions with GABA-A receptors, can have enormous implications for the treatment and/or management of nociception and pain. Afferent nociceptive information is processed in the superficial spinal dorsal horn (SDH), Rexed’s laminae I & II, and transferred to higher Fructose centers for conscious pain perception. At the spinal level, actions of GABA at axo-axonic synapses, cause presynaptic inhibition (PI) via primary afferent depolarization (PAD), which impedes further conduction of action potentials [8], [9], [33]. Modulation of PAD offers a potential mechanism for analgesia. The extent of PAD, when enhanced via combined effects of neighboring pain pathways or by actions of opioids and associated peptides, produces analgesic actions, by modulating evoked transmitter release and filtering nociceptive input [34], [36], [37]. GABA-B receptors, present at the axon terminals, seem to produce analgesic effects by regulating neurotransmitter release. The slower inhibition mediated by GABA-B receptors, have made them a preferable target for treating neuropathic pain and inflammation [32]. This is, however, also true for GABA-C receptors. They exhibit slower kinetics (>200ms), which seem to match with the duration of PAD itself and have a greater sensitivity to GABA, making them more suitable for regulating pain. While GABA-C ρ1 receptors have been implicated in peripheral pain [30], knockout studies reveal a central role for these receptors in regulating pain [2], [45]. In the present study, we examined if GABA-Cρ2 receptors play a role in pain in the CNS, and whether they are expressed presynaptically in the substantia gelatinosa of the lumbar dorsal horn of the spinal cord.
    Material and methods Male Wistar rats weighing 60–130g were purchased from the Animal Care Center, The University of British Columbia. All experiments were performed in accordance to the guidelines of the Canadian Council on Animal Care and the University of British Columbia committee on Animal Care. Rats were anaesthetized with 4% halothane and either drugs or saline were administered intracisternally, in a 100μl bolus. For injections, the hair covering the cleft formed between the occipital crest and anterior edge of the atlas vertebrae was trimmed off for a clear visualization of the injection site. The head of the rat was then held down at a 45° angle and a 25G needle was inserted into the cleft. With the occipital bone as a guide, the needle was lowered until it reached the cisterna magna. Drugs, TPMPA, CACA, CACA+TPMPA, isoguvacine (IG), IG+TPMPA or saline, were administered. TPMPA was purchased from Tocris Bioscience. CACA and IG were purchased from Sigma–Aldrich Co. LLC. An injection of 5% Chicago Sky Blue dye solution was also performed to visualize the distribution of the above agents, and confirm the location of the injection site.