ABSTRACT
Neuropathic pain results from injury or dysfunction of the central or peripheral nervous system. The treatment of neuropathic pain is challenging, in part because of its multiple etiologies. The present study explores combinations of the analgesic tramadol and each of four anticonvulsants in the treatment of surgically induced (ligation of the L5 spinal nerve) allodynia in rats. Each of the five drugs studied exhibited a dose-dependent antiallodynic effect. When studied in combination, tramadol and each of two of the anticonvulsants (topiramate and RWJ-333369) interacted synergistically at all three ratios studied, whereas tramadol and each of the other two anticonvulsants (gabapentin and lamotrigine) exhibited a synergistic antiallodynic effect at only one of three ratios investigated. In addition, tramadol and topiramate were found to interact synergistically in a nociceptive pain model, the mouse hot-plate test. These studies suggest the benefit of using combinations of analgesics and anticonvulsants in the relief of neuropathic pain.
Subject(s)
Analgesics/administration & dosage , Anticonvulsants/administration & dosage , Hyperesthesia/drug therapy , Neuralgia/drug therapy , Pain Measurement/drug effects , Tramadol/administration & dosage , Animals , Drug Therapy, Combination , Hyperesthesia/diagnosis , Hyperesthesia/etiology , Male , Neuralgia/complications , Neuralgia/diagnosis , Rats , Rats, Sprague-Dawley , Touch , Treatment OutcomeABSTRACT
A small series of novel, imidazoles 4 have been prepared that exhibit very good binding affinities for the delta and mu opioid receptors (ORs), as well as demonstrate potent agonist functional activity at the delta OR. Representative imidazole 4a (K(i) delta = 0.9 nM; K(i) mu = 55 nM; K(i) kappa = 124 nM; EC(50) delta =13-25 nM) was further profiled for OR related in vivo effects. Compound 4a reduced gastrointestinal (GI) propulsive motility in a dose-dependent and naloxone-reversible manner, based on the results of the mouse glass bead expulsion test (3, 5, and 10 mg/kg, ip) and the mouse fecal pellet output test (1 and 3 mg/kg, ip). Compound 4a showed no analgesic activity as measured by the mouse abdominal irritant test (MAIT) when dosed at 100 mg/kg, sc, but did show significant MAIT activity at doses of both 10 microg (40% inhibition) and 100 microg (100% inhibition) when dosed intracerebroventricularly (icv). Taken together, these in vivo results suggest that 4a acts peripherally when dosed systemically, and that these prototypical compounds may prove promising as medicinal leads for GI indications.
Subject(s)
Imidazoles/chemical synthesis , Receptors, Opioid/agonists , Abdominal Muscles/drug effects , Abdominal Muscles/physiology , Analgesics/chemical synthesis , Analgesics/chemistry , Analgesics/pharmacology , Animals , CHO Cells , Cricetinae , Gastrointestinal Diseases/drug therapy , Gastrointestinal Motility/drug effects , Imidazoles/chemistry , Imidazoles/pharmacology , In Vitro Techniques , Injections, Intraventricular , Injections, Subcutaneous , Male , Mice , Models, Molecular , Molecular Conformation , Muscle Contraction/drug effects , Pain Measurement , Rats , Rats, Wistar , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/agonists , Structure-Activity RelationshipABSTRACT
A series of N,N-dialkyl-4-(9-aryltropanylidenemethyl)benzamides was prepared. The lead compounds, 15a and 15c, exhibited extremely high affinity for the delta opioid receptor with excellent selectivity versus the micro opioid receptor. They were full agonists at the delta opioid receptor, as assessed by stimulation of GTPgammaS binding, and displayed antinociceptive activity.
Subject(s)
Analgesics, Opioid/pharmacology , Benzamides/pharmacology , Receptors, Opioid, delta/agonists , Analgesics, Opioid/chemistry , Benzamides/chemistry , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Structure-Activity RelationshipABSTRACT
The tertiary amide delta opioid agonist 2 is a potent antinociceptive agent. Compound 2 was metabolized in vitro and in vivo to secondary amide 3, a potent and selective micro opioid agonist. The SAR of a series of N-alkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides was examined.
Subject(s)
Analgesics/pharmacology , Benzamides/pharmacology , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/agonists , Analgesics/chemistry , Benzamides/chemistry , Structure-Activity RelationshipABSTRACT
Pretreatment of mice with a subcutaneous (s.c.) injection of LiCl (1, 3, 10 mmol/kg) 18 h prior to testing produced dose-related attenuation of the reciprocal hindlimb scratching (RHS) response induced by intrathecal (i.t.) administration of pilocarpine. LiCl (10 mmol/kg, 424 mg/kg) pretreatment shifted the pilocarpine (2 microg)-induced RHS dose-response curve about 5-fold to the right compared to vehicle-injected controls (ED(50) = 2.97 and 0.56 microg, respectively). Coadministration of inositol-1,4,5-trisphosphate (IP(3); 5, 10, 20 microg), but not inositol hexaphosphate (0.03-3 microg), myo-inositol (10 microg) or EDTA (1.33 microg), produced dose-related reversal of the LiCl effect. IP(3) administration alone neither produced RHS nor enhanced the pilocarpine-induced RHS in animals not pretreated with LiCl. These findings provide in vivo evidence for a possible link between RHS and a LiCl-sensitive, possibly phosphoinositide-related, effector pathway.
