The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Dec 2013
Nerve injury increases GluA2-lacking AMPA receptor prevalence in spinal cords: functional significance and signaling mechanisms.
The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are critically involved in the excitatory synaptic transmission, and blocking AMPARs at the spinal level reverses neuropathic pain. However, little is known about changes in the composition of synaptic AMPARs in the spinal dorsal horn after peripheral nerve injury. AMPARs lacking the GluA2 subunit are permeable to Ca(2+), and their currents show unique inward rectification. ⋯ In addition, blocking GluA2-lacking AMPARs at the spinal cord level reduced nerve injury-induced pain hypersensitivity. Our study suggests that nerve injury increases GluA2 internalization and the prevalence of GluA2-lacking AMPARs in the spinal dorsal horn to maintain chronic neuropathic pain. Increased prevalence of spinal GluA2-lacking AMPARs in neuropathic pain is mediated by NMDARs and subsequent stimulation of calpain and calcineurin signaling.
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J. Pharmacol. Exp. Ther. · Dec 2013
The delta-opioid receptor is sufficient, but not necessary, for spinal opioid-adrenergic analgesic synergy.
Spinal administration of opioid and α2-adrenergic receptor (α2AR) agonists produces analgesia, and agonists interact synergistically when coadministered. The molecular mechanism underlying this synergy is largely unknown. Pharmacological studies have identified both the delta and the mu-opioid receptors (DOR and MOR) as candidate receptors capable of interacting synergistically with α2AR agonists. ⋯ Clonidine was synergistic with morphine in both mouse strains. DAMGO did not synergize with clonidine in either strain. These findings confirm that although other opioid receptors can interact synergistically with α2AR agonists, DOR is sufficient for spinal opioid-adrenergic interactions.
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J. Pharmacol. Exp. Ther. · Dec 2013
Spinal-supraspinal and intrinsic μ-opioid receptor agonist-norepinephrine reuptake inhibitor (MOR-NRI) synergy of tapentadol in diabetic heat hyperalgesia in mice.
Tapentadol is a μ-opioid receptor (MOR) agonist and norepinephrine reuptake inhibitor (NRI) with established efficacy in neuropathic pain in patients and intrinsic synergistic interaction of both mechanisms as demonstrated in rodents. In diabetic mice, we analyzed the central antihyperalgesic activity, the occurrence of site-site interaction, as well as the spinal contribution of opioid and noradrenergic mechanisms in a hotplate test. Tapentadol (0.1-3.16 µg/animal) showed full efficacy after intrathecal as well as after intracerebroventricular administration (ED50 0.42 µg/animal i.t., 0.18 µg/animal i.c.v.). ⋯ Spinal administration of the opioid antagonist naloxone or the α2-adrenoceptor antagonist yohimbine before systemic administration of equianalgesic doses of tapentadol (1 mg/kg i.p.) or morphine (3.16 mg/kg i.p.) revealed pronounced influence on opioidergic and noradrenergic pathways for both compounds. Tapentadol was more sensitive toward both antagonists than was morphine, with median effective dose values of 0.75 and 1.72 ng/animal i.t. naloxone and 1.56 and 2.04 ng/animal i.t. yohimbine, respectively. It is suggested that the antihyperalgesic action of systemically administered tapentadol is based on opioid spinal-supraspinal synergy, as well as intrinsic spinally mediated MOR-NRI synergy.
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J. Pharmacol. Exp. Ther. · Dec 2013
Effect of delay on self-administration of remifentanil under a drug versus drug choice procedure in rhesus monkeys.
Drug abuse can be conceptualized as excessive choice of drug over other reinforcers, and factors that affect drug taking can be examined experimentally using choice procedures. This study examined the impact of reinforcer delay on self-administration of the μ-opioid receptor agonist remifentanil in rhesus monkeys (n = 4) lever pressing under a concurrent fixed-ratio 30 schedule. Responding on either lever delivered an intravenous infusion of either remifentanil or saline. ⋯ These data demonstrate that delaying the delivery of an opioid receptor agonist can significantly affect its reinforcing effectiveness. The imposition of a delay reduces the effectiveness of large doses of drug to maintain responding and increases the effectiveness of immediately available commodities, including smaller doses of drug. Increased reinforcing effectiveness of smaller doses of drug in the context of other delayed reinforcers might contribute to the development and maintenance of opioid abuse.