Indirect involvement of α-adrenoceptors in the mechanical antihypersensitivity effect induced by the spinally administered imidazoline I receptor ligand LNP599 in a rat model of experimental neuropathy.

Here we assess whether neuropathic pain hypersensitivity is attenuated by spinal administration of the imidazoline I-receptor agonist LNP599 and whether the attenuation involves co-activation of α-adrenoceptors. Spared nerve injury (SNI) model of neuropathy was used to induce mechanical hypersensitivity in male and female rats with a chronic catheter for intrathecal drug administrations. Mechanical sensitivity and heat nociception were assessed behaviorally in the injured limb.

Spinal TRPA1 Contributes to the Mechanical Hypersensitivity Effect Induced by Netrin-1.

Netrin-1, a chemoattractant expressed by floor plate cells, and one of its receptors (deleted in colorectal cancer) has been associated with pronociceptive actions in a number of pain conditions. Here, we addressed the question of whether spinal TRPC4/C5 or TRPA1 are among the downstream receptors contributing to pronociceptive actions induced by netrin-1. The experiments were performed on rats using a chronic intrathecal catheter for administration of netrin-1 and antagonists of TRPC4/C5 or TRPA1.

Spinal mechanisms contributing to the development of pain hypersensitivity induced by sphingolipids in the rat.

Background: Earlier studies show that endogenous sphingolipids can induce pain hypersensitivity, activation of spinal astrocytes, release of proinflammatory cytokines and activation of TRPM3 channel. Here we studied whether the development of pain hypersensitivity induced by sphingolipids in the spinal cord can be prevented by pharmacological inhibition of potential downstream mechanisms that we hypothesized to include TRPM3, σ and NMDA receptors, gap junctions and D-amino acid oxidase.

Methods: Experiments were performed in adult male rats with a chronic intrathecal catheter for spinal drug administrations.

Fadolmidine - Favourable adverse effects profile for spinal analgesia suggested by in vitro and in vivo models.

Fadolmidine is an α-adrenoceptor full agonist developed for spinal analgesia with a local mode of action. The purpose of this study was to demonstrate the safety of fadolmidine on known α-adrenoceptor-related effects: kidney function, urodynamics and cardiovascular variables. Furthermore, the binding affinity of fadolmidine for the 5-HT receptor prompted functional studies on 5-HT.

Amygdaloid administration of tetrapentylammonium attenuates development of pain and anxiety-like behavior following peripheral nerve injury.

Background: The central amygdaloid nucleus (CeA) is involved in processing and descending regulation of pain. Amygdaloid mechanisms underlying pain processing and control are poorly known. Here we tested the hypothesis that perioperative CeA administration of tetrapentylammonium (TPA), a non-selective THIK-1 channel blocker and thereby inhibitor of microglia, attenuates development of chronic neuropathic pain and comorbid anxiety-like behavior.

TRPA1 Antagonists for Pain Relief.

Here, we review the literature assessing the role of transient receptor potential ankyrin 1 (TRPA1), a calcium-permeable non-selective cation channel, in various types of pain conditions. In the nervous system, TRPA1 is expressed in a subpopulation of nociceptive primary sensory neurons, astroglia, oligodendrocytes and Schwann cells. In peripheral terminals of nociceptive primary sensory neurons, it is involved in the transduction of potentially harmful stimuli and in their central terminals it is involved in amplification of nociceptive transmission.

Transient receptor potential ankyrin 1 (TRPA1) ion channel in the pathophysiology of peripheral diabetic neuropathy.

Background Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel permeable to calcium that is expressed on pain-mediating primary afferent nerve fibers. Here we review recent experimental evidence supporting the hypothesis that activation of the TRPA1 channel by reactive compounds generated in diabetes mellitus, such as 4-hydroxynonenal and methylglyoxal, exerts an important role in the pathophysiology of peripheral diabetic neuropathy (PDN). The hypothesis includes development of the early diabetic pain hypersensitivity and the later loss of cutaneous nerve endings of pain fibers and their dysfunction, which are hallmarks of peripheral diabetic neuropathy (PDN).

Regulation of neuropathic pain behavior by amygdaloid TRPC4/C5 channels.

Pain per se may increase anxiety and conversely, anxiety may increase pain. Therefore, a positive feedback loop between anxiety and pain possibly contributes to pain and suffering in some pathophysiological pain conditions, such as that induced by peripheral nerve injury. Recent results indicate that transient receptor channels 4 and 5 (TRPC4/C5) in the amygdala have anxiogenic effects in rodents, while their role in chronic pain conditions is not known.

TRPA1: a transducer and amplifier of pain and inflammation.

The transient receptor potential ankyrin 1 (TRPA1) ion channel on peripheral terminals of nociceptive primary afferent nerve fibres contributes to the transduction of noxious stimuli to electrical signals, while on central endings in the spinal dorsal horn, it amplifies transmission to spinal interneurons and projection neurons. The centrally propagating nociceptive signal that is induced and amplified by TRPA1 not only elicits pain sensation but also contributes to peripheral neurogenic inflammation through a peripheral axon reflex or a centrally mediated back propagating dorsal root reflex that releases vasoactive agents from sensory neurons in the periphery. Endogenous TRPA1 agonists that are generated under various pathophysiological conditions both in the periphery and in the spinal cord have TRPA1-mediated pro-nociceptive and pro-inflammatory effects.

Pharmacological characterisation of a structurally novel α2C-adrenoceptor antagonist ORM-10921 and its effects in neuropsychiatric models.

The α2-adrenoceptors (ARs) are important modulators of a wide array of physiological responses. As only a few selective compounds for the three α2-AR subtypes (α2A , α2B and α2C ) have been available, the pharmacological profile of a new α2C-selective AR antagonist ORM-10921 is reported. Standard in vitro receptor assays and antagonism of α2, and α1-AR agonist-evoked responses in vivo were used to demonstrate the α2C-AR selectivity for ORM-10921 which was tested in established behavioural models related to schizophrenia and cognitive dysfunction with an emphasis on pharmacologically induced hypoglutamatergic state by phencyclidine or MK-801.

Dissociated modulation of conditioned place-preference and mechanical hypersensitivity by a TRPA1 channel antagonist in peripheral neuropathy.

Transient receptor potential ankyrin 1 (TRPA1) channel antagonists have suppressed mechanical hypersensitivity in peripheral neuropathy, while their effect on ongoing neuropathic pain is not yet known. Here, we assessed whether blocking the TRPA1 channel induces place-preference, an index for the relief of ongoing pain, in two experimental rat models of peripheral neuropathy. Diabetic neuropathy was induced by streptozotocin and spared nerve injury (SNI) model of neuropathy by ligation of two sciatic nerve branches.

Transient receptor potential ankyrin 1 ion channel contributes to guarding pain and mechanical hypersensitivity in a rat model of postoperative pain.

Background: The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed on nociceptive primary afferent nerve fibers. On the distal ending, it is involved in transduction of noxious stimuli, and on the proximal ending (within the spinal dorsal horn), it regulates transmission of nociceptive signals. Here we studied whether the cutaneous or spinal TRPA1 ion channel contributes to mechanical hypersensitivity or guarding, an index of spontaneous pain, in an experimental model of postoperative pain in the rat.

Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy.

Peripheral diabetic neuropathy (PDN) is a devastating complication of diabetes mellitus (DM). Here we test the hypothesis that the transient receptor potential ankyrin 1 (TRPA1) ion channel on primary afferent nerve fibers is involved in the pathogenesis of PDN, due to sustained activation by reactive compounds generated in DM. DM was induced by streptozotocin in rats that were treated daily for 28 days with a TRPA1 channel antagonist (Chembridge-5861528) or vehicle.

TRPA1 ion channel in the spinal dorsal horn as a therapeutic target in central pain hypersensitivity and cutaneous neurogenic inflammation.

Transient receptor potential ankyrin 1 (TRPA1) is a non-selective, calcium permeable cation channel expressed by a subpopulation of primary afferent nociceptive nerve fibers. On peripheral nerve endings, TRPA1 channel contributes to transduction of chemical and physical stimuli, whereas on the central endings in the spinal dorsal horn, which is the topic of this brief review, it regulates glutamatergic transmission. Blockade of the spinal TRPA1 channel has attenuated mechanical pain hypersensitivity particularly to low-intensity stimulation in various pathophysiological conditions, whereas blockade of the TRPA1 channel-mediated regulation of transmission failed to influence baseline pain behavior in healthy control animals.

Spinal transient receptor potential ankyrin 1 channel contributes to central pain hypersensitivity in various pathophysiological conditions in the rat.

The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed on nociceptive primary afferent neurons. On the proximal nerve ending within the spinal dorsal horn, TRPA1 regulates transmission to spinal interneurons, and thereby pain hypersensitivity. Here we assessed whether the contribution of the spinal TRPA1 channel to pain hypersensitivity varies with the experimental pain model, properties of test stimulation or the behavioral pain response.

Spinal TRPA1 ion channels contribute to cutaneous neurogenic inflammation in the rat.

In the spinal dorsal horn, TRPA1 ion channels on central terminals of peptidergic primary afferent nerve fibers regulate transmission to glutamatergic and GABAergic interneurons. Here we determine the cutaneous anti-inflammatory effect of a spinally administered TRPA1 channel antagonist to test the hypothesis that spinal TRPA1 channels contribute to cutaneous neurogenic inflammation induced by sustained noxious stimulation. According to the hypothesis, spinal TRPA1 channels facilitate transmission of injury discharge to GABAergic interneurons that induce a dorsal root reflex, which results in increased release of proinflammatory compounds in the skin.

Roles of cutaneous versus spinal TRPA1 channels in mechanical hypersensitivity in the diabetic or mustard oil-treated non-diabetic rat.

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.

Attenuation of mechanical hypersensitivity by an antagonist of the TRPA1 ion channel in diabetic animals.

Background: The TRPA1 ion channel modulates excitability of nociceptors, and it may be activated by compounds resulting from oxidative insults. Diabetes mellitus produces oxidative stress and sensory neuropathy. The authors tested the hypothesis that diabetes-induced endogenous compounds acting on the TRPA1 ion channel contribute to development and maintenance of mechanical hypersensitivity.

In vitro and in vivo profiling of fadolmidine, a novel potent alpha(2)-adrenoceptor agonist with local mode of action.

Alpha2-adrenergic receptors (alpha2-adrenoceptors) mediate various physiological actions of endogenous catecholamines in the central and peripheral nervous systems being involved in alertness, heart rate regulation, vasomotor control and nociceptive processing. In the present study, the pharmacological profile of a novel alpha2-adrenoceptor agonist, fadolmidine, was studied in various in vitro and in vivo assays and compared to the well characterised alpha2-adrenoceptor agonist, dexmedetomidine. Fadolmidine displayed high affinity and full agonist efficacy at all three human alpha2-adrenoceptor subtypes (A, B and C) in transfected CHO cells with EC50 values (nM) of 0.