Consistent sex-dependent effects of PKMζ gene ablation and pharmacological inhibition on the maintenance of referred pain.

Background: Persistently active PKMζ has been implicated in maintaining spinal nociceptive sensitization that underlies pain hypersensitivity. However, evidence for PKMζ in the maintenance of pain hypersensitivity comes exclusively from short-term studies in males using pharmacological agents of questionable selectivity. The present study examines the contribution of PKMζ to long-lasting allodynia associated with neuropathic, inflammatory, or referred visceral and muscle pain in males and females using pharmacological inhibition or genetic ablation.

Effects of topical combinations of clonidine and pentoxifylline on capsaicin-induced allodynia and postcapsaicin tourniquet-induced pain in healthy volunteers: a double-blind, randomized, controlled study.

This double-blind randomized controlled study was designed to evaluate the analgesic effects of topical treatments with clonidine (CLON) and pentoxifylline (PTX) tested alone or as low- and high-dose combinations in a human experimental model of pain. Of 69 healthy subjects aged 18 to 60 years, 23 each were randomly allocated to low-dose (0.04% + 2%) and high-dose (0.

Topical combinations to treat microvascular dysfunction of chronic postischemia pain.

Background: Growing evidence indicates that patients with complex regional pain syndrome (CRPS) exhibit tissue abnormalities caused by microvascular dysfunction in the blood vessels of skin, muscle, and nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in an animal model of CRPS. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors given to increase arterial blood flow, combined with either phosphatidic acid (PA) or phosphodiesterase (PDE) inhibitors to increase capillary blood flow, would effectively reduce allodynia and signs of microvascular dysfunction in the animal model of chronic pain.

Pentoxifylline reduces chronic post-ischaemia pain by alleviating microvascular dysfunction.

Background: Microvascular dysfunction and ischaemia in muscle play a role in the development of cutaneous tactile allodynia in chronic post-ischaemia pain (CPIP). Hence, studies were designed to assess whether pentoxifylline (PTX), a vasodilator and haemorrheologic agent, relieves allodynia in CPIP rats by alleviating microvascular dysfunction.

Methods: Laser Doppler flowmetry of plantar blood flow was used to examine the effects of PTX on CPIP-induced alterations in post-occlusive reactive hyperaemia (reflecting microvascular dysfunction), and von Frey testing was used to examine its effects on CPIP-induced allodynia.

Topical combinations aimed at treating microvascular dysfunction reduce allodynia in rat models of CRPS-I and neuropathic pain.

Unlabelled: Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α(2)-adrenergic (α(2)A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain.

Cutaneous tactile allodynia associated with microvascular dysfunction in muscle.

Background: Cutaneous tactile allodynia, or painful hypersensitivity to mechanical stimulation of the skin, is typically associated with neuropathic pain, although also present in chronic pain patients who do not have evidence of nerve injury. We examine whether deep tissue microvascular dysfunction, a feature common in chronic non-neuropathic pain, contributes to allodynia.

Results: Persistent cutaneous allodynia is produced in rats following a hind paw ischemia-reperfusion injury that induces microvascular dysfunction, including arterial vasospasms and capillary slow flow/no-reflow, in muscle.

Newer GABA derivatives for the treatment of epilepsy including febrile seizures: a bioisosteric approach.

The present study aims at design and synthesis of newer gamma-aminobutyric acid (GABA) derivatives with the combination of thiosemicarbazone and GABA pharmacophores in order to develop newer anticonvulsants. The reported compounds were designed as bioisosteric analogues of GABA semicarbazones. The structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis.

An update on GABA analogs for CNS drug discovery.

GABA (gamma-aminobutyric acid) is one of the major inhibitory transmitters in the central nervous system of mammals. GABA is not transported efficiently into the brain from the bloodstream (i.e.

Newer N-phthaloyl GABA derivatives with antiallodynic and antihyperalgesic activities in both sciatic nerve and spinal nerve ligation models of neuropathic pain.

Background: There is considerable research evidence supporting a palliative role for gamma-aminobutyric acid (GABA)-ergic neurotransmission and voltage-gated sodium channel blockade in neuropathic pain conditions. Hence, the present study was undertaken to assess the peripheral analgesic, antiallodynic and antihyperalgesic activities of the synthesized structural analogues of GABA.

Methods: The screening study included acute tissue injury, chronic constriction injury (CCI), and spinal nerve ligation (SNL) models of neuropathic pain.

Discovery of 4-aminobutyric acid derivatives possessing anticonvulsant and antinociceptive activities: a hybrid pharmacophore approach.

Antiepileptic drugs are often utilized in the treatment of neuropathic pain. The present study aims at the design and synthesis of newer gamma-aminobutyric acid (GABA) derivatives with the combination of aryl semicarbazone and the GABA pharmacophores in order to develop a multifunctional drug useful in the treatment of neurological disorders like epilepsy and neuropathic pain. Various GABA semicarbazones were synthesized and screened for anticonvulsant, peripheral analgesic, antiallodynic, and antihyperalgesic activities.

Neuropathic pain: strategies in drug discovery and treatment.

Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system. In contrast to acute nociceptive pain, the cascade of events that arise following peripheral nerve injury leads to a maintained abnormality in the sensory system, resulting in an abnormal pain phenomenon that can be grossly debilitating. At present, there are very few effective and well-tolerated therapies for neuropathic pain.

Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide and hydrazone pharmacophore.

Two series of pharmacophoric hybrids of phthalimide-GABA-anilides/hydrazones were designed and synthesized and evaluated for their anticonvulsant and neurotoxic properties. The structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. Initial anticonvulsant screening was performed using intraperitoneal (i.

Synthesis of N4-(2,4-dimethylphenyl) semicarbazones as 4-aminobutyrate aminotransferase inhibitors.

Several 2,4-dimethylphenyl substituted semicarbazones were synthesized in three steps involving aryl urea and aryl semicarbazide formation. The structures were confirmed by spectral and elemental analyses. All the compounds were evaluated for anticonvulsant activity by using a series of test models, including maximal electroshock seizure, subcutaneous pentylenetetrazole and subcutaneous strychnine seizure threshold tests.

Synthesis and structure-activity relationship on anticonvulsant aryl semicarbazones.

Seven series of various substituted aryl semicarbazones were synthesized and evaluated for anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure threshold tests. A comprehensive structure-activity relationship was derived comparing the substituents on the aryl ring and in the carbimino terminal. Generally the order of activity was 4-F > 2-Br = 3-Br = 4-Cl > 4-CH(3) > 4-Br > 3-Cl > 3-CH(3) with respect to the primary aryl group.

Synthesis of aryl semicarbazones as potential anticonvulsant agents.

A series of 4-ethoxyphenyl semicarbazones (1-10) have been synthesized using an appropriate synthetic route and characterized by elemental analyses and spectral data. The anticonvulsant activity of all the synthesized compounds was evaluated against maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method.

Ion channels as important targets for antiepileptic drug design.

Ion channels have a critical role in the function of the nervous system, where they instigate and conduct nerve impulses by asserting control over the voltage potential across the plasma membrane. Propagation of electrical impulses occurs by opening of voltage-gated ion channels. Ion channel blockers prevent this from occurring, and can therefore be used in the treatment of central nervous system disorders and neuropathic pain.

Synthesis and anticonvulsant and neurotoxicity evaluation of N4-phthalimido phenyl (thio) semicarbazides.

The phenyl (thio) semicarbazide derivatives of phthalimido pharmacophore were synthesized and evaluated for their anticonvulsant and neurotoxic properties. Initial anticonvulsant screening was performed using intraperitoneal (i.p.