naloxone and Peripheral-Nerve-Injuries

An effective and safe treatment of insomnia in patients with neuropathic pain remains an unmet need. Melatonin and its analogs have been shown to have both analgesic and hypnotic effects; however, capacity of them on sleep disturbance with neuropathic pain as well as the precise mechanism is unclear.. The present study evaluated effects of piromelatine, a novel melatonin receptor agonist, on sleep disturbance in a neuropathic pain-like condition as well as the underlying mechanisms.. A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSL) was employed. The antinociceptive and hypnotic effects of piromelatine were evaluated by measurement of thermal hyperalgesia, mechanical allodynia, and electroencephalogram (EEG) recordings in PSL mice. Pharmacological approaches were used to clarify the mechanisms of action of piromelatine.. PSL significantly lowered thermal and mechanical latencies and decreased non-rapid eye movement (NREM) sleep, and PSL mice exhibited sleep fragmentation. Treatment with 25, 50, or 100 mg/kg of piromelatine significantly prolonged thermal and mechanical latencies and increased NREM sleep. Moreover, the antinociceptive effect of piromelatine was prevented by melatonin antagonist luzindole, opioid receptor antagonist naloxone, or 5HT1A receptor antagonist WAY-100635. The hypnotic effect of piromelatine was blocked by luzindole but neither by naloxone nor WAY-100635.. These data indicate that piromelatine is an effective treatment for both neuropathic pain and sleep disturbance in PSL mice. The antinociceptive effect of piromelatine is likely mediated by melatonin, opioid, and 5HT1A receptors; however, the hypnotic effect of piromelatine appears to be mediated by melatonin receptors.

Topics: Analgesics; Animals; Disease Models, Animal; Hyperalgesia; Hypnotics and Sedatives; Indoles; Male; Melatonin; Mice; Naloxone; Narcotic Antagonists; Neuralgia; Pain Measurement; Peripheral Nerve Injuries; Piperazines; Pyrans; Pyridines; Receptor, Serotonin, 5-HT1A; Receptors, Melatonin; Receptors, Opioid; Sciatic Nerve; Serotonin Antagonists; Sleep Wake Disorders; Tryptamines

Transforming growth factor-β1 (TGF-β1) protects against neuroinflammatory events underlying neuropathic pain. TGF-β signaling enhancement is a phenotypic characteristic of mice lacking the TGF-β pseudoreceptor BAMBI (BMP and activin membrane-bound inhibitor), which leads to an increased synaptic release of opioid peptides and to a naloxone-reversible hypoalgesic/antiallodynic phenotype. Herein, we investigated the following: (1) the effects of BAMBI deficiency on opioid receptor expression, functional efficacy, and analgesic responses to endogenous and exogenous opioids; and (2) the involvement of the opioid system in the antiallodynic effect of TGF-β1. BAMBI-KO mice were subjected to neuropathic pain by sciatic nerve crash injury (SNI). Gene (PCR) and protein (Western blot) expressions of μ- and δ-opioid receptors were determined in the spinal cord. The inhibitory effects of agonists on the adenylyl cyclase pathway were investigated. Two weeks after SNI, wild-type mice developed mechanical allodynia and the functionality of μ-opioid receptors was reduced. By this time, BAMBI-KO mice were protected against allodynia and exhibited increased expression and function of opioid receptors. Four weeks after SNI, when mice of both genotypes had developed neuropathic pain, the analgesic responses induced by morphine and RB101 (an inhibitor of enkephalin-degrading enzymes, which increases the synaptic levels of enkephalins) were enhanced in BAMBI-KO mice. Similar results were obtained in the formalin-induced chemical-inflammatory pain model. Subcutaneous TGF-β1 infusion prevented pain development after SNI. The antiallodynic effect of TGF-β1 was naloxone-sensitive. In conclusion, modulation of the endogenous opioid system by TGF-β signaling improves the analgesic effectiveness of exogenous and endogenous opioids under pathological pain conditions.

Topics: Adenylyl Cyclase Inhibitors; Analgesia; Analgesics, Opioid; Animals; Disulfides; Hyperalgesia; Infusions, Subcutaneous; Membrane Proteins; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Neuralgia; Peripheral Nerve Injuries; Phenylalanine; Receptors, Opioid, delta; Receptors, Opioid, mu; Sciatic Nerve; Signal Transduction; Spinal Cord; Transforming Growth Factor beta

Physical injury, including surgery, can result in chronic pain; yet chronic pain following childbirth, including cesarean delivery in women, is rare. The mechanisms involved in this protection by pregnancy or delivery have not been explored.. We examined the effect of pregnancy and delivery on hypersensitivity to mechanical stimuli of the rat hindpaw induced by peripheral nerve injury (spinal nerve ligation) and after intrathecal oxytocin, atosiban, and naloxone. Additionally, oxytocin concentration in lumbar spinal cerebrospinal fluid was determined.. Spinal nerve ligation performed at mid-pregnancy resulted in similar hypersensitivity to nonpregnant controls, but hypersensitivity partially resolved beginning after delivery. Removal of pups after delivery prevented this partial resolution. Cerebrospinal fluid concentrations of oxytocin were greater in normal postpartum rats prior to weaning. To examine the effect of injury at the time of delivery rather than during pregnancy, spinal nerve ligation was performed within 24 h of delivery. This resulted in acute hypersensitivity that partially resolved over the next 2-3 weeks. Weaning of pups resulted only in a temporary return of hypersensitivity. Intrathecal oxytocin effectively reversed the hypersensitivity following separation of the pups. Postpartum resolution of hypersensitivity was transiently abolished by intrathecal injection of the oxytocin receptor antagonist, atosiban.. These results suggest that the postpartum period rather than pregnancy protects against chronic hypersensitivity from peripheral nerve injury and that this protection may reflect sustained oxytocin signaling in the central nervous system during this period.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Female; Hormone Antagonists; Hypersensitivity; Injections, Spinal; Naloxone; Narcotic Antagonists; Oxytocics; Oxytocin; Peripheral Nerve Injuries; Physical Stimulation; Postpartum Period; Rats; Rats, Sprague-Dawley; Spinal Nerves; Vasotocin; Weaning

The analgesic properties and mechanisms of loperamide hydrochloride, a peripherally acting opioid receptor agonist, in neuropathic pain warrant further investigation.. We examined the effects of systemic or local administration of loperamide on heat and mechanical hyperalgesia in rats after an L5 spinal nerve ligation (SNL)..  (1) Systemic loperamide (0.3-10 mg/kg, subcutaneous in the back) dose dependently reversed heat hyperalgesia in SNL rats, but did not produce thermal analgesia. Systemic loperamide (3 mg/kg) did not induce thermal antinociception in naïve rats; (2) systemic loperamide-induced anti-heat hyperalgesia was blocked by pretreatment with intraperitoneal naloxone methiodide (5 mg/kg), but not by intraperitoneal naltrindole (5 mg/kg) or intrathecal naltrexone (20 μg/10 μL); (3) local administration of loperamide (150 μg), but not vehicle, into plantar or dorsal hind paw tissue induced thermal analgesia in SNL rats and thermal antinociception in naïve rats; (4) the analgesic effect of intraplantar loperamide (150 μg/15 μL) in SNL rats at 45 min, but not 10 min, post-injection was blocked by pretreatment with an intraplantar injection of naltrexone (75 μg/10 μL); (5) systemic (3.0 mg/kg) and local (150 μg) loperamide reduced the exaggerated duration of hind paw elevation to noxious pinprick stimuli in SNL rats. Intraplantar injection of loperamide also decreased the frequency of pinprick-evoked response in naïve rats.. These findings suggest that both systemic and local administration of loperamide induce an opioid receptor-dependent inhibition of heat and mechanical hyperalgesia in nerve-injured rats, but that local paw administration of loperamide also induces thermal and mechanical antinociception.

Topics: Analgesia; Analgesics; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Hot Temperature; Hyperalgesia; Loperamide; Male; Naloxone; Pain Measurement; Pain Threshold; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley; Spinal Nerves

Local microvessels of peripheral nerve trunks (vasa nervorum) dilate following capsaicin-induced inflammation or local nerve trunk injury. In previous work, we observed that morphine blocked capsaicin-induced dilation of vasa nervorum presumably through the action of local opioid receptors. In the present work, we studied injury-related hyperemia of the rat sciatic vasa nervorum using laser Doppler and hydrogen clearance microelectrode measurements of local perfusion. Systemic morphine reversed hyperemia by vasoconstricting both extrinsic and intrinsic microvessels supplying 48-h-old "neuroma" preparations or crush zones of peripheral nerve trunks. Morphine did not constrict microvessels of contralateral uninjured or sham exposed but uninjured sciatic nerves. In contrast to the injured nerves, contralateral uninjured nerves exposed to morphine frequently had a rise in local perfusion, indicating vasodilation. The vasoconstrictive actions of morphine were blocked by pretreatment with naloxone and were not mimicked by saline injections alone. Systemic doses of selective opioid agonists to mu-, kappa-, and delta-receptors also selectively constricted microvessels of injured nerves. Local blood flow in older experimental neuromas at 7 days had partial sensitivity to morphine, whereas at 14 days perfusion flow was not influenced by morphine. Exogenous opioids dampen early but not later inflammatory microvasodilation and could have important influences on the nerve regenerative milieu.

Topics: Animals; Erythrocytes; Laser-Doppler Flowmetry; Male; Microcirculation; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Nerve Crush; Neuroma; Peripheral Nerve Injuries; Peripheral Nerves; Peripheral Nervous System Neoplasms; Rats; Rats, Sprague-Dawley; Reference Values; Sciatic Nerve; Time Factors

The effects of intraperitoneal (I.P.), intracerebroventricular (ICV) and intrathecal (IT) opiates were studied in the rat neuropathic pain model of Kim and Chung. Dose dependent reduction of allodynia was observed after I.P. and ICV morphine, but not after IT morphine, IT or ICV c[D-pen2 D-pen5]enkephalin (DPDPE) (delta agonist), or IT or ICV U50488H (kappa agonist). The effects of ICV morphine were blocked by I.P. naloxone, but not by IT methysergide, phentolamine or 8-sulfophenyltheophylline. Catalepsy (immobility) was observed after IT, ICV and IT morphine but this was not reliably associated with a reduction of allodynia. I.P. and ICV morphine may thus reduce tactile allodynia via supraspinal, but not spinal, mu opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Opioid; Animals; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Spinal; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Pain; Peripheral Nerve Injuries; Pyrrolidines; Rats; Rats, Sprague-Dawley