Neuropharmacology
-
P2X receptors are ligand-gated ion channels activated by ATP that are widely expressed in the organism and regulate many physiological functions. We have studied the effect of progesterone (PROG) on native P2X receptors present in rat dorsal root ganglion (DRG) neurons and on recombinant P2X receptors expressed in HEK293 cells or Xenopus laevis oocytes. The effects of PROG were observed and already maximal during the first coapplication with ATP and did not need any preincubation of the cells with PROG, indicating a fast mechanism of action. ⋯ We conclude that PROG selectively potentiates homomeric P2X2 receptors and, in contrast with dehydroepiandrosterone (DHEA), discriminates between homomeric and heteromeric P2X2-containing receptors. This might have important physiological implications since the P2X2 subunit is the most widely distributed P2X subunit in the organism. Moreover, DHEA and PROG might be useful tools to clarify the distribution and the role of native homo- and heteromeric P2X2 receptors.
-
Pre-clinical evidence demonstrates that neuropathic spinal cord injury (SCI) pain is maintained by a number of neurobiological mechanisms, suggesting that treatments directed at several pain-related targets may be more advantageous compared to a treatment focused on a single target. The current study evaluated the efficacy of the non-opiate analgesic acetaminophen, which has several putative analgesic mechanisms, combined with analgesic drugs used to treat neuropathic pain in a rat model of below-level neuropathic SCI pain. Following an acute compression of the mid-thoracic spinal cord, rats exhibited robust hind paw hypersensitivity to innocuous mechanical stimulation. ⋯ The results imply that modulation of the endocannabinoid system in addition to other mechanisms mediate the synergistic antinociceptive effects of acetaminophen combinations. Despite the presence of a cannabinoid mechanism, synergism was not present in all acetaminophen combinations. The combination of currently available drugs may be an appropriate option in ameliorating neuropathic SCI pain if single drug therapy is ineffective.
-
Previous results indicate that intaperitoneal administration of a TRPA1 channel antagonist attenuates diabetic hypersensitivity. We studied whether the antihypersensitivity effect induced by a TRPA1 channel antagonist in diabetic animals is explained by action on the TRPA1 channel in the skin, the spinal cord, or both. For comparison, we determined the contribution of cutaneous and spinal TRPA1 channels to development of hypersensitivity induced by topical administration of mustard oil in healthy controls. ⋯ I.t. administration of CHEM (10 microg) in controls produced a strong antihypersensitivity effect adjacent to the mustard oil-treated area (site of secondary hyperalgesia), while it failed to influence hypersensitivity at the mustard oil-treated area (site of primary hyperalgesia). A reversible antagonism of the rat TRPA1 channel by CHEM was verified using in vitro patch clamp recordings. The results suggest that while cutaneous TRPA1 channels contribute to mechanical hypersensitivity induced by diabetes or topical mustard oil, spinal TRPA1 channels, probably on central terminals of primary afferent nerve fibers, play an important role in maintenance of mechanical hypersensitivity in these conditions.
-
The 6-methoxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid, DM2, exerts anti-absence activity and blocks Cav3.1 channel, a T-type voltage-dependent Ca(2+) channel subtype, in vitro. The current study investigated the effect of intra-ventrolateral periaqueductal grey (VLPAG) administration of DM2 on formalin-induced nocifensive responses in rats. In addition, the effect of intra-VLPAG microinjection of DM2 on the ongoing and tail flick-related activities of rostral ventromedial medulla (RVM) cell population was also investigated. ⋯ Finally, DM2 administration did not produce any adverse cardiovascular effects as blood pressure and heart rate remained unchanged. In conclusion, DM2 plays an analgesic role in vivo and changes RVM cell activity, consistent with antinociception. These effects were even more potent than those elicited by ethosuximide treatments.