Spinal astrocytes in superficial laminae gate brainstem descending control of mechanosensory hypersensitivity.

Astrocytes are critical regulators of CNS function and are proposed to be heterogeneous in the developing brain and spinal cord. Here we identify a population of astrocytes located in the superficial laminae of the spinal dorsal horn (SDH) in adults that is genetically defined by Hes5. In vivo imaging revealed that noxious stimulation by intraplantar capsaicin injection activated Hes5 SDH astrocytes via α-adrenoceptors (α-ARs) through descending noradrenergic signaling from the locus coeruleus.

Peripheral nerve injury in rats induces alternations in choice behavior associated with food reinforcement.

Operant methods that allow animals to avoid painful stimuli are interpreted to assess the aversive quality of pain; however, such measurements require investigator-initiated stimuli to animals. Here we developed a shuttle maze test to repeatedly assess activity associated nociception without forced stimulation. Rats ambulate back and forth between two treat feeders by taking either a short route with a prickly surfaced arch or a longer route with a smooth floor.

Strategies to Treat Chronic Pain and Strengthen Impaired Descending Noradrenergic Inhibitory System.

Gabapentinoids (gabapentin and pregabalin) and antidepressants (tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors) are often used to treat chronic pain. The descending noradrenergic inhibitory system from the locus coeruleus (LC) to the dorsal horn of the spinal cord plays an important role in the analgesic mechanisms of these drugs. Gabapentinoids activate the LC by inhibiting the release of γ-aminobutyric acid (GABA) and inducing the release of glutamate, thereby increasing noradrenaline levels in the spinal cord.

Novel agonist of αβ* neuronal nicotinic receptor with antinociceptive efficacy in rodent models of acute and chronic pain.

Objective: To demonstrate the antinociceptive and antihypersensitivity mechanisms of Cris-104 (1-{2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]ethyl}piperidine), a novel selective αβ* nicotinic acetylcholine receptor (nAChR) agonist, in rodent acute/inflammatory and chronic pain models.

Materials And Methods: Hot-plate and formalin tests in mice were used to examine Cris-104-induced antinociceptive effects on thermal/inflammatory pain. Cris-104 effects on hypersensitivity, norepinephrine (NE) release in the spinal dorsal horn, and neuronal activity in the locus coeruleus (LC) were examined in rats with lumbar spinal nerve ligation using behavioral, microdialysis, and extracellular recording methods.

Descending Noradrenergic Inhibition: An Important Mechanism of Gabapentin Analgesia in Neuropathic Pain.

Gabapentinoids are effective in a wide range of animal pain models and in patients with neuropathic pain and has become one of first-line treatments for neuropathic pain. Because spinal plasticity and sensitization have been intensely studied in neuropathic pain, most laboratory studies have focused on actions of gabapentinoids in the spinal cord, where they reduce primary afferent traffic and excitation of spinal nociceptive neurons, via interaction with α2δ subunits of voltage-gated Ca channels. However, a recent clinical study questioned the relevance of this in vitro and in vivo rodent studies by demonstrating a complete lack of clinical efficacy of intrathecal gabapentin in patients with chronic pain.

Plasticity and Function of Spinal Oxytocin and Vasopressin Signaling during Recovery from Surgery with Nerve Injury.

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Recovery from pain after surgery is faster after cesarean delivery than after other abdominal procedures. The authors hypothesized that recovery in rats after surgery could be reversed by antagonism of spinal oxytocin or vasopressin receptors, that there may be a sex difference, and that spinal oxytocin innervation could change after surgery.

Methods: Male and female rats underwent partial spinal nerve ligation surgery.

Psychosocial Stress Delays Recovery of Postoperative Pain Following Incisional Surgery in the Rat.

Psychosocial factors such as anxiety, depression and catastrophizing, commonly associated with established chronic pain, also may be associated with an increased risk of chronic postsurgical pain (CPSP) when present preoperatively. We used a repeat social defeat (RSD) paradigm to induce psychosocial stress in rodents prior to incisional surgery of the paw. Mixed effects growth curve models were utilized to examine resolution of mechanical hypersensitivity in rats for four weeks following surgery.

Blockade of α2-adrenergic or metabotropic glutamate receptors induces glutamate release in the locus coeruleus to activate descending inhibition in rats with chronic neuropathic hypersensitivity.

Locus coeruleus (LC)-spinal noradrenergic projections are important to endogenous analgesic mechanisms and can be activated by local glutamate signaling in the LC. The current study examined the local glutamatergic, GABAergic, and noradrenergic influences on glutamate release in the LC and noradrenergic descending inhibition in rats 6 weeks after spinal nerve ligation (SNL). Intra-LC injection of the α2 adrenoceptor antagonist idazoxan or the group 2 metabotropic glutamate receptor (mGluR) antagonist (RS)-α-Methyl-4-tetrazolylphenylglycine (MTPG) increased withdrawal thresholds in SNL animals and this was reversed by the blockade of α-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid (AMPA) receptors in the LC or α2-adrenoceptors in the spinal cord, but not in normal animals.

Antinociception induced by a novel α adrenergic receptor agonist in rodents acute and chronic pain models.

The mechanisms and antinociceptive effects of a novel α adrenoceptor agonist, 3-(2-chloro-6-fluorobenzil)-imidazolinide-2,4-dione (PT-31) were investigated using animal models of acute and chronic pain. The effects of PT-31 on pain responses were examined using hot plate and formalin tests in mice and spinal nerve ligation (SNL)-induced hyperalgesia in rats. The effects of antagonists acting on α adrenoceptor were assessed to investigate the interaction of these pathways upon PT-31 induced antinociception.

ATP release from bladder urothelium and serosa in a rat model of partial bladder outlet obstruction.

Overactive bladder is one of the major health problem especially in elderly people. Adenosine triphosphate (ATP) is released from urinary bladder cells and acts as a smooth muscle contraction and sensory signal in micturition but little is known about the role of ATP release in the pathophysiology of overactive bladder. To assess the relationship between ATP and overactive bladder, we used a partial bladder outlet obstruction (pBOO) model in rats.

Gabapentin loses efficacy over time after nerve injury in rats: role of glutamate transporter-1 in the locus coeruleus.

Despite being one of the first-choice analgesics for chronic neuropathic pain, gabapentin sometimes fails to provide analgesia, but the mechanisms for this lack of efficacy is unclear. Rats with nerve injury including L5-L6 spinal nerve ligation (SNL) respond uniformly and well to gabapentin, but many of these studies are performed within just a few weeks of injury, questioning their relevance to chronic neuropathic pain. In this study, intraperitoneal gabapentin showed a time-dependently reduction in antihypersensitivity after SNL, associated with downregulation of astroglial glutamate transporter-1 (GLT-1) in the locus coeruleus (LC).

Disruption of Spinal Noradrenergic Activation Delays Recovery of Acute Incision-Induced Hypersensitivity and Increases Spinal Glial Activation in the Rat.

Unlabelled: Results of clinical studies suggest that descending inhibitory controls from the brainstem are important for speeding recovery from pain after surgery. We examined the effects of destroying spinally projecting noradrenergic neurons via intrathecally administered antibody to dopamine β-hydroxylase conjugated to saporin (DβH-saporin) on recovery in an acute incisional pain model. Mechanical and thermal paw withdrawal thresholds and nonevoked spontaneous guarding scores were tested for several weeks postoperatively and analyzed using mixed effects growth curve modeling.

Down-regulation of astroglial glutamate transporter-1 in the locus coeruleus impairs pain-evoked endogenous analgesia in rats.

Descending noradrenergic inhibition to the spinal cord from the locus coeruleus (LC) is an important endogenous pain-relief mechanism which can be activated by local glutamate signaling. Here we tested whether dysregulation of extracellular glutamate level in the LC induced by down-regulating astroglial glutamate transporter-1(GLT-1) impairs endogenous analgesia. In rats treated with repeated LC injections of GLT-1 selective or non-targeting small interfering RNA (siRNA), a subdermal injection of capsaicin was used to examine noxious stimulation-induced analgesia (NSIA), evoked LC glutamate and spinal noradrenaline release, and evoked LC neuronal activity.

Impaired Pain-evoked Analgesia after Nerve Injury in Rats Reflects Altered Glutamate Regulation in the Locus Coeruleus.

Background: Patients with neuropathic pain show reduced endogenous analgesia induced by a conditioned noxious stimulus. Here, the authors tested whether peripheral nerve injury impairs descending noradrenergic inhibition from the locus coeruleus (LC) after L5-L6 spinal nerve ligation (SNL) in rats.

Methods: A subdermal injection of capsaicin was used to examine noxious stimulation-induced analgesia (NSIA), evoked LC glutamate and spinal noradrenaline release, and evoked LC neuronal activity in normal and SNL rats.

Nerve injury induces a new profile of tactile and mechanical nociceptor input from undamaged peripheral afferents.

Chronic pain after nerve injury is often accompanied by hypersensitivity to mechanical stimuli, yet whether this reflects altered input, altered processing, or both remains unclear. Spinal nerve ligation or transection results in hypersensitivity to mechanical stimuli in skin innervated by adjacent dorsal root ganglia, but no previous study has quantified the changes in receptive field properties of these neurons in vivo. To address this, we recorded intracellularly from L4 dorsal root ganglion neurons of anesthetized young adult rats, 1 wk after L5 partial spinal nerve ligation (pSNL) or sham surgery.

Fast-conducting mechanoreceptors contribute to withdrawal behavior in normal and nerve injured rats.

Fast-conducting myelinated high-threshold mechanoreceptors (AHTMR) are largely thought to transmit acute nociception from the periphery. However, their roles in normal withdrawal and in nerve injury-induced hyperalgesia are less well accepted. Modulation of this subpopulation of peripheral neurons would help define their roles in withdrawal behaviors.

Peripheral nerve injury and gabapentin, but not their combination, impair attentional behavior via direct effects on noradrenergic signaling in the brain.

Chronic pain after peripheral nerve damage is often accompanied by a reduction in prefrontal cortex (PFC)-related cognitive functions, which are regulated by noradrenaline, released from efferents originating in the locus coeruleus (LC). L5 to L6 spinal nerve ligation (SNL) in rats increased tissue content and extracellular concentrations of noradrenaline in microdialysates from the PFC, and impaired attentional level in the novel object recognition test. Systemic gabapentin, commonly used to treat chronic pain, impaired the novel object recognition task in normal but not SNL animals.

Gabapentin increases extracellular glutamatergic level in the locus coeruleus via astroglial glutamate transporter-dependent mechanisms.

Gabapentin has shown to be effective in animals and humans with acute postoperative and chronic pain. Yet the mechanisms by which gabapentin reduces pain have not been fully addressed. The current study performed in vivo microdialysis in the locus coeruleus (LC) in normal and spinal nerve ligated (SNL) rats to examine the effect of gabapentin on extracellular glutamate concentration and its mechanisms of action with focus on presynaptic GABA-B receptors, astroglial glutamate transporter-1 (GLT-1), and interactions with α2δ subunits of voltage-gated Ca(2+) channels and endogenous noradrenaline.

Valproate prevents dysregulation of spinal glutamate and reduces the development of hypersensitivity in rats after peripheral nerve injury.

Unlabelled: The present study examined whether the histone deacetylase inhibitor valproate prevents downregulation of glutamate transporters in the primary cultured astrocytes and in the spinal cord after L5-L6 spinal nerve ligation (SNL) and whether this action of valproate on spinal glutamate transporters prevents spinal glutamate dysregulation and development of hypersensitivity after SNL. In cultured astrocytes, valproate prevented downregulation of glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter in a concentration-dependent manner. Repeated oral administration of valproate reduced the development of hypersensitivity and prevented the downregulation of spinal GLT-1 and glutamate-aspartate transporter expression in rats after SNL, but did not affect mechanical nociception and expression of those transporters in normal rats.

Reversal of peripheral nerve injury-induced hypersensitivity in the postpartum period: role of spinal oxytocin.

Background: Physical injury, including surgery, can result in chronic pain; yet chronic pain following childbirth, including cesarean delivery in women, is rare. The mechanisms involved in this protection by pregnancy or delivery have not been explored.

Methods: We examined the effect of pregnancy and delivery on hypersensitivity to mechanical stimuli of the rat hindpaw induced by peripheral nerve injury (spinal nerve ligation) and after intrathecal oxytocin, atosiban, and naloxone.

Relief of hypersensitivity after nerve injury from systemic donepezil involves spinal cholinergic and γ-aminobutyric acid mechanisms.

Background: Evoking spinal release of acetylcholine (ACh) produces antinociception in normal animals and reduces hypersensitivity after nerve injury, and some studies suggest that ACh-mediated analgesia relies on γ-aminobutyric acid (GABA)-ergic signaling in the spinal cord. In this study, the authors tested the spinal mechanisms underlying the antihypersensitivity effects of donepezil, a central nervous system-penetrating cholinesterase inhibitor, in a rat model of neuropathic pain.

Methods: Male Sprague-Dawley rats were anesthetized, and L5 spinal nerve ligation was performed unilaterally.

Ondansetron reverses antihypersensitivity from clonidine in rats after peripheral nerve injury: role of γ-aminobutyric acid in α2-adrenoceptor and 5-HT3 serotonin receptor analgesia.

Introduction: Monoaminergic pathways, impinging an α2-adrenoceptors and 5-HT3 serotonin receptors, modulate nociceptive transmission, but their mechanisms and interactions after neuropathic injury are unknown. Here we examine these interactions in rodents after nerve injury.

Methods: Male Sprague-Dawley rats following L5-L6 spinal nerve ligation (SNL) were used for either behavioral testing, in vivo microdialysis for γ-aminobutyric acid (GABA) and acetylcholine release, or synaptosome preparation for GABA release.

Gabapentin inhibits γ-amino butyric acid release in the locus coeruleus but not in the spinal dorsal horn after peripheral nerve injury in rats.

Background: Gabapentin reduces acute postoperative and chronic neuropathic pain, but its sites and mechanisms of action are unclear. Based on previous electrophysiologic studies, the authors tested whether gabapentin reduced γ-amino butyric acid (GABA) release in the locus coeruleus (LC), a major site of descending inhibition, rather than in the spinal cord.

Methods: Male Sprague-Dawley rats with or without L5-L6 spinal nerve ligation (SNL) were used.