Chronic constriction injury (CCI) of the rodent sciatic nerve causes light touch mechanical sensitivity (allodynia) and leads to activation of spinal astrocytes and microglia. The endocannabinoid system includes the cannabinoid receptor 1 (CB1R) present on neurons and the cannabinoid receptor 2 (CB2R) present mostly on immune cells. CB2R agonists, like AM1710, believed to exert analgesic effects through CB2R actions, are effective in controlling pathological pain states in animal models. However, activation of CB1R could be partly responsible for the analgesic effects of AM1710 through non-specific binding. We sought to determine whether AM1710 could lead to anti-allodynia and produce changes in spinal pro- and anti-inflammatory protein IR in mice lacking functional CB1R (CB1R-/-). We first characterized the allodynia profile of CB1R+/+, CB1R+/- and CB1R-/- mice. Following CCI, CB1R-/- mice displayed allodynia similar to wild-type and heterozygous littermates, with reliable 27-day chronic allodynia. Following baseline threshold assessment, mice underwent sham or CCI surgery, and thresholds were reassessed 5 and 12 days later. Mice were given an intraperitoneal (i.p.) injection of either AM1710 (25 mg/kg/ml) or equivolume vehicle. Following behavioral reassessment at 25 min after injection, spinal tissues were harvested. AM1710, given i.p. reversed CCI-induced allodynia in CB1R-KO mice to control levels. Next, we sought to determine an effective timecourse for AM1710 (5 μg) delivered intrathecally (i.t.) to reverse allodynia in wild type mice. Allodynia reversal occurred 2 hours after administration. Finally, we sought to determine if spinal CB1R were responsible for intrathecal AM170 effects. We found AM1710 robustly reversed chronic allodynia in CB1R-/- mice. Ongoing studies using spectral analysis of IR will examine glial activation, and pro- and anti-inflammatory cytokine changes in these tissues. Supported by NIH grants: NIDA 018156, GM60201, and funded in part by the Dedicated Health Research Funds from the University of New Mexico School of Medicine.

The phase diagrams of EuFe2-xCoxAs2 (0 <= x <= 0.4) and EuFe2As2-yPy (0 <= y <= 0.43) are investigated by Eu2+ electron spin resonance (ESR) in single crystals. From the temperature dependence of the linewidth Delta H(T) of the exchange narrowed ESR line, the spin-density wave (SDW) (T < T-SDW) and the normal metallic regime (T > T-SDW) are clearly distinguished. AtT > T-SDW the isotropic linear increase of the linewidth is driven by the Korringa relaxation which measures the conduction-electron density of states at the Fermi level. For T < T-SDW the anisotropy probes the local ligand field, while the coupling to the conduction electrons is strongly weakened. With increasing substitution of x or y the transition temperature T-SDW decreases linearly accompanied by a linear decrease of the Korringa-relaxation rate from 8 Oe/K at x = y = 0 down to 3 Oe/K at the onset of superconductivity. Forx > 0.2 andy > 0.3 it remains nearly constant. Comparative ESR measurements on single crystals of the Eu diluted SDWcompound Eu0.2Sr0.8Fe2As2 and superconducting (SC) Eu0.22Sr0.78Fe1.72Co0.28As2 corroborate the leading influence of the ligand field on the Eu2+ spin relaxation in the SDW regime as well as the Korringa relaxation in the normal metallic regime. A coherence peak is not detected in the latter compound below T-c = 21 K, which is in agreement with the expected complex anisotropic SC gap structure. In contrast, indications for phase coexistence and BCS-type superconductivity are found in EuFe2As1.57P0.43.

Electron spin resonance measurements in EuFe2As2 single crystals revealed an absorption spectrum of a single resonance with Dysonian line shape. Above the spin-density wave (SDW) transition at T-SDW = 190 K the spectra are isotropic and the Eu spins relax via the conduction electrons resulting in a Korringa-type increase in the linewidth. Below T-SDW, a distinct anisotropy develops and the relaxation behavior of the Eu spins changes drastically into one with characteristic properties of a magnetic insulating system, where dipolar and crystal-field interactions dominate. This indicates a spatial confinement of the conduction electrons to the FeAs layers in the SDW state.

Recent changes in understanding chronic neuropathic pain now include a role for glial cells (microglia and astrocytes) in the central nervous system (CNS). Marijuana contains compounds that have been shown to activate the well-characterized cannabinoid 1 receptor (CB1R) found on neurons and the recently characterized cannabinoid 2 receptor (CB2R) found on glia in the CNS. Compounds that selectively activate CB2R in the spinal cord reduce pathological pain after peripheral nerve injury. CB2R activation is not known to cause the psychotropic effects associated with CB1R agonists and may be a candidate target to control chronic pain. Chronic constriction injury (CCI) of the rodent sciatic nerve leads to light touch mechanical sensitivity (allodynia). Systemic selective CB2R agonists like AM1241 mediate chronic pain. We sought to further characterize whether a more restricted peri-spinal (intrathecal, i.t.) injection of AM1241 (A) and a structurally distinct highly selective CB2R agonist (B) are also efficacious in reducing chronic allodynia after CCI. Baseline (BL) responses to light touch were assessed (von Frey test) after animals were habituated to the testing environment, and 3 and 10 days after CCI. Behavior was re-assessed at 30-min intervals for 3 hr, 5 hr and 24 hr after i.t. injection of equivolume vehicle (10ul), A (10ug) or B (10ug) in sham or CCI-treated rats. Both A and B robustly reversed allodynia with allodynia returning by 1.5 and 3 hr after A or B injection, respectively. Ongoing studies will determine a maximal therapeutic dose for both CB2R agonists, the presence of CBRs and levels of inflammatory factors after i.t. injection of A and B. These data support that CB2R activation in the spinal cord leads to neuropathic pain control that may have clinical relevance in treating chronic pain. (Supported by NIH grants: NIDA 018156, GM60201.)

Electron spin resonance measurements in EuFe2As2 single crystals revealed an absorption spectrum of a single resonance with Dysonian lineshape. Above the spin-density wave transition at T_SDW = 190 K the spectra are isotropic and the spin relaxation is strongly coupled to the CEs resulting in a Korringa-like increase of the linewidth. Below T_SDW, a distinct anisotropy develops and the relaxation behavior of the Eu spins changes drastically into one with characteristic properties of a magnetic insulating system, where dipolar and crystal-field interactions dominate. This indicates a spatial confinement of the conduction electrons to the FeAs layers in the SDW state.