ABSTRACT
Orexin-A and orexin-B are endogenous ligands of orexin receptors that contain orexin-1 and orexin-2. Activation of the orexinergic system can produce antinociceptive effects in acute inflammatory, mono-neuropathic, and postoperative pain animal models, though the effects of orexins on diabetic neuropathic pain have not been previously investigated. In this study, we studied the anti-hyperalgesic effects of intrathecally administered orexins in a streptozotocin-induced diabetic rat. First, dose-dependent effects were investigated by measuring hind paw withdrawal thresholds in response to noxious-heat and punctate stimuli, after which orexin levels in the cerebrospinal fluid of diabetic rats were measured and compared with those of normal rats using a radioimmunoassay method. The functional role of spinal orexin-1 receptors with the anti-hyperalgesic effects of orexins was also investigated using intrathecal pretreatment with SB-334867, a selective orexin-1 receptor antagonist. Intrathecally administered orexins produced an antinociceptive effect in diabetic rats, however, not in normal rats, though the orexin levels in the cerebrospinal fluid of diabetic rats were similar to those in normal rats. In addition, the anti-hyperalgesic effects of orexins were significantly inhibited by pretreatment with SB-334867. These findings demonstrate that the anti-hyperalgesic effects of orexins in diabetic rats are unlikely due to any direct effect by the supplement on decreased endogenous orexins in the cerebrospinal fluid and that orexin-1 receptors in the spinal cord may be involved in the modulation of nociceptive transmission in diabetic neuropathy. We conclude that the spinal orexinergic system may be a possible target for elucidating the mechanisms of diabetes-induced hyperalgesia.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetic Neuropathies/drug therapy , Intracellular Signaling Peptides and Proteins/administration & dosage , Neuropeptides/administration & dosage , Receptors, Neuropeptide/physiology , Spinal Cord/drug effects , Urea/analogs & derivatives , Animals , Behavior, Animal , Benzoxazoles/pharmacology , Diabetes Mellitus, Experimental/complications , Diabetic Neuropathies/cerebrospinal fluid , Diabetic Neuropathies/etiology , Dose-Response Relationship, Drug , Drug Interactions , Hyperalgesia/classification , Hyperalgesia/drug therapy , Injections, Spinal/methods , Intracellular Signaling Peptides and Proteins/cerebrospinal fluid , Male , Naloxone/pharmacology , Naphthyridines , Narcotic Antagonists/pharmacology , Neuropeptides/cerebrospinal fluid , Orexin Receptors , Orexins , Pain Measurement , Pain Threshold/drug effects , Radioimmunoassay/methods , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled , Streptozocin , Time Factors , Urea/pharmacologyABSTRACT
Etodolac, a cyclooxygenase-2 inhibitor, may alleviate nociceptive pain and inhibit the activation of osteoclasts. The aim of the present study was to determine whether etodolac can alleviate heat-evoked hyperalgesia and investigate its possible protective effects on osteoporosis induced by chronic constriction injury (CCI) in rats. A CCI to the sciatic nerve was performed, after which the rats received etodolac orally in a volume of 2 ml at 0, 1, and 10 mg/kg/day for 1 to 5 weeks following surgery (experiment 1); at 0 and 10 mg/kg/day for 1 day to 5 weeks following surgery (experiment 2); and at 0 mg/kg/day for 1 to 5 weeks, 10 mg/kg/day for 1 to 2 weeks after surgery, or 10 mg/kg/day for 1 to 3 weeks after surgery (experiment 3). Paw withdrawal latency after exposure to heat, bone mineral content (BMC) and bone mineral density (BMD) in the whole tibial bone, and the number of tartrate resistant acid phosphate (TRAP)-positive multinucleated osteoclasts were measured. Etodolac alleviated heat-evoked hyperalgesia in the CCI rats and the increase in number of TRAP-positive multinucleated osteoclasts on the CCI-side was abrogated, however, it did not inhibit the decrease of BMC and BMD on the CCI-side. Our results suggest that etodolac is useful for treatment of neuropathic pain.
Subject(s)
Etodolac/pharmacology , Isoenzymes/antagonists & inhibitors , Neuralgia/drug therapy , Osteoporosis/drug therapy , Peripheral Nerves/drug effects , Peripheral Nervous System Diseases/drug therapy , Acid Phosphatase/drug effects , Acid Phosphatase/metabolism , Animals , Bone Density/drug effects , Bone Density/physiology , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Disease Models, Animal , Hyperalgesia/drug therapy , Hyperalgesia/metabolism , Hyperalgesia/physiopathology , Isoenzymes/drug effects , Isoenzymes/metabolism , Ligation , Neuralgia/metabolism , Neuralgia/physiopathology , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteoporosis/metabolism , Osteoporosis/physiopathology , Pain Measurement , Peripheral Nerves/metabolism , Peripheral Nervous System Diseases/metabolism , Peripheral Nervous System Diseases/physiopathology , Prostaglandin-Endoperoxide Synthases/metabolism , Rats , Rats, Sprague-Dawley , Reaction Time/drug effects , Reaction Time/physiology , Sciatic Neuropathy/drug therapy , Sciatic Neuropathy/metabolism , Sciatic Neuropathy/physiopathology , Tartrate-Resistant Acid Phosphatase , Up-Regulation/drug effects , Up-Regulation/physiologyABSTRACT
JTC-801, a nociceptin antagonist, may alleviate neuropathic pain because nociceptin has been shown to produce pain modulation. We report that JTC-801 alleviates heat-evoked hyperalgesia and investigated the possible protective effect on osteoporosis induced by chronic constriction injury (CCI) in rats. JTC-801 was given orally to rats with CCI at 0% (vehicle), 0.03% (low dose), or 0.06% (high dose) in food. Paw withdrawal latency (PWL) to heat, bone mineral content (BMC) and bone mineral density (BMD) of the whole tibial bone were measured. JTC-801 dose-dependently normalized PWL. Although JTC-801 did not inhibit a CCI-induced decrease in BMC and BMD, it inhibited an increase in the number of osteoclasts in the JTC-801 groups. JTC-801, given orally in food, alleviated heat-evoked hyperalgesia in CCI rats, suggesting that it is useful for the treatment of neuropathic pain.
Subject(s)
Aminoquinolines/administration & dosage , Benzamides/administration & dosage , Disease Models, Animal , Hyperalgesia/drug therapy , Opioid Peptides/antagonists & inhibitors , Pain Measurement/drug effects , Animals , Hyperalgesia/pathology , Male , Rats , Rats, Sprague-Dawley , NociceptinABSTRACT
Orexin-A, a hypothalamic peptide found in the neurons of the lateral hypothalamus, has been shown to modulate pain. We examined whether orexin could alleviate heat-evoked hyperalgesia in rats caused by chronic constriction injury (CCI) of the sciatic nerve. Orexin-A, orexin-B, the vehicle, or orexin-A-antiserum was intrathecally administered to CCI rats. Paw withdrawal latency (PWL) was measured from 30 to 300 minutes after injection, which was repeated for 2 days. Orexin-A administration normalized deltaPWL (PWL in the CCI side minus PWL in the control side) and inhibited heat-evoked hyperalgesia in CCI rats, while orexin-A antiserum inhibited the normalization of heat-evoked hyperalgesia caused by orexin-A two-fold. In contrast, orexin-B had no significant effect. These results suggest that orexin-A may be applicable for treatment of neuropathic pain.
Subject(s)
Analgesics/therapeutic use , Carrier Proteins/therapeutic use , Hyperalgesia/drug therapy , Intracellular Signaling Peptides and Proteins , Neuropeptides/therapeutic use , Pain/drug therapy , Sciatic Neuropathy/drug therapy , Analgesics/administration & dosage , Animals , Carrier Proteins/administration & dosage , Disease Models, Animal , Hot Temperature , Hyperalgesia/etiology , Injections, Spinal , Neuropeptides/administration & dosage , Orexins , Pain/physiopathology , Rats , Sciatic Neuropathy/etiology , Sciatic Neuropathy/physiopathologyABSTRACT
Chronic constriction injury (CCI) to the rat sciatic nerve results in osteopenia in the affected hind limb. One possible mechanism for this osteopenia is neurogenic inflammation, in which neuropeptides, represented by substance P (SP), are involved. We attempted to determine whether capsaicin treatment, which can deplete SP from nerve terminals, is effective in inhibiting osteopenia induced by CCI. Capsaicin (total dose, 125 mg/kg) or the vehicle alone was given intraperitoneally to adult rats 2 days before (Experiment 1) and 7 days after (Experiment 2) CCI surgery. Paw withdrawal latency (PWL) was measured prior to and every week for 5 weeks after surgery. Bone mineral density (BMD) and the number of osteoclasts in tibial bones were determined 5 weeks after surgery. In rats treated with the vehicle, BMD on the CCI side was decreased significantly, while the number of osteoclasts was significantly increased in both experiments. Capsaicin treatment either before or 1 week after surgery inhibited the decreases in BMD as well as the increase in the number of osteoclasts on the CCI side. PWL for the CCI side in the vehicle group was significantly shorter than for the sham side in both experiments. However, capsaicin treatment before surgery resolved heat hyperalgesia in Experiment 1, while in Experiment 2, even though heat hyperalgesia developed on the CCI side, it was resolved by capsaicin treatment. The results of the present study show that capsaicin inhibits the development of osteopenia as well as heat hyperalgesia induced by CCI. They also support our hypothesis that neurogenic SP release is involved in the pathogenesis of bony changes induced by CCI.