norbinaltorphimine and Chronic-Disease

Topics: Abdominal Pain; Analgesics; Animals; Cells, Cultured; Chronic Disease; Dose-Response Relationship, Drug; Drug Design; HEK293 Cells; Helianthus; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Peptides, Cyclic; Plant Extracts; Receptors, Opioid, kappa; Seeds; Structure-Activity Relationship

The amygdala plays an important role in the processing of chronic pain and pain memory formation. Particularly, it is involved in the emotional and affective components of the pain circuitry. The role of kappa opioid receptors in these pain conditions is only partly known. The present study investigates the effect of kappa receptor activation on synaptic transmission and synaptic plasticity in the amygdala.. Electrophysiological in vitro experiments were carried out in brain slices of male C57BL/6JOlaHsd mice. The effect of the kappa opioid receptor agonist U50,488H (5 microM) and the selective kappa opioid receptor antagonist nor-BNI (3 microM) on field potential (FP) amplitude and the induction of long-term potentiation (LTP) in the basolateral amygdala (BLA) was examined.. High frequency stimulation (HFS) of afferents in the lateral amygdala with two trains of 100 pulses at 50 Hz increased the FP amplitudes to 119+/-2% (mean+/-SEM; n=6) in the BLA. U50,488H decreased synaptic transmission (baseline: 100+/-0.5%; U50,488H: 86.3+/-2.4%; n=6) and blocked the induction of LTP (U50,488H: 100+/-4.1%; HFS: 102.6+/-7%; n=6). The effect on synaptic transmission and on LTP was completely reversed or prevented by application of nor-BNI, which itself had no effect on synaptic transmission or the induction of LTP.. Kappa opioid receptor activation decreases synaptic transmission and inhibits the induction of LTP in the BLA of the mouse. These findings may be associated with the effects of kappa opioid agonists in chronic pain and pain memory formation.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amygdala; Analgesics, Non-Narcotic; Animals; Chronic Disease; Electric Stimulation; Electrophysiology; Emotions; Extinction, Psychological; Long-Term Potentiation; Male; Mice; Mice, Inbred C57BL; Naltrexone; Pain; Receptors, Opioid, kappa; Synaptic Transmission

Low-dose naloxone-precipitated withdrawal hyperalgesia is a reliable indicator of physical dependence after chronic morphine treatment. A remarkably similar long-lasting (>3-4 h) hyperalgesia is evoked by injection of a low dose of naloxone (10 microg/kg, s.c.) in naïve mice after acute pretreatment with the glycolipid, GM1 ganglioside (1 mg/kg) (measured by warm-water-immersion tail-flick assays). GM1 treatment markedly increases the efficacy of excitatory Gs-coupled opioid receptor signaling in nociceptive neurons. Co-treatment with an ultra-low-dose (0.1 ng/kg, s.c.) of the broad-spectrum opioid receptor antagonist, naltrexone or the selective kappa opioid receptor antagonist, nor-binaltorphimine, blocks naloxone-evoked hyperalgesia in GM1-pretreated naïve mice and unmasks prominent, long-lasting (>4 h) inhibitory opioid receptor-mediated analgesia. This unmasked analgesia can be rapidly blocked by injection after 1-2 h of a high dose of naltrexone (10 mg/kg) or nor-binaltorphimine (0.1 mg/kg). Because no exogenous opioid is administered to GM1-treated mice, we suggest that naloxone may evoke hyperalgesia by inducing release of endogenous bimodally acting opioid agonists from neurons in nociceptive networks by antagonizing putative presynaptic inhibitory opioid autoreceptors that "gate" the release of endogenous opioids. In the absence of exogenous opioids, the specific pharmacological manipulations utilized in our tail-flick assays on GM1-treated mice provide a novel bioassay to detect the release of endogenous bimodally acting (excitatory/inhibitory) opioid agonists. Because mu excitatory opioid receptor signaling is blocked by ultra-low doses of naloxone, the higher doses of naloxone that evoke hyperalgesia in GM1-treated mice cannot be mediated by activation of mu opioid receptors. Co-treatment with ultra-low-dose naltrexone or nor-binaltorphimine may selectively block signaling by endogenous GM1-sensitized excitatory kappa opioid receptors, unmasking inhibitory kappa opioid receptor signaling, and converting endogenous opioid receptor-mediated hyperalgesia to analgesia. Co-treatment with kelatorphan stabilizes putative endogenous opioid peptide agonists released by naloxone in GM1-treated mice, so that analgesia is evoked rather than hyperalgesia. Acute treatment of chronic morphine-dependent mice with ultra-low-dose naltrexone (0.1 ng/kg) results in remarkably similar rapid blocking of naloxone (10 microg/kg)-precipitated withdrawal hyperalgesia

Topics: Analgesics, Opioid; Animals; Chronic Disease; Dipeptides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; G(M1) Ganglioside; Hyperalgesia; Male; Mice; Morphine; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Opioid Peptides; Receptors, Opioid, kappa; Substance Withdrawal Syndrome

This study examined the role of kappa opioid receptors (KOR) in the mechanism underlying tolerance to the analgesic effects of morphine induced by chronic pain. The analgesic effect of morphine (10 mg kg(-1)), estimated by the tail-flick test in mice, gradually decreased during repeated daily morphine treatment. A significant decrease in the analgesic effect of morphine was seen on the fifth day of repeated morphine treatment compared with the first day. Chronic pain was induced by subcutaneous administration of 2% formalin into the dorsal part of the left hind paw, which significantly inhibited development of tolerance to morphine analgesia. The effect of formalin-induced pain on inhibition of morphine tolerance was reversed by the KOR antagonist nor-binaltorphimine. Furthermore, an antisense oligodeoxynucleotide, but not a missense oligodeoxynucleotide, against KOR completely suppressed the inhibitory effect of formalin-induced pain on morphine tolerance. Naltrindole, an antagonist of delta opioid receptor, did not affect chronic-pain-induced tolerance to morphine. Our findings show that the inhibitory effect of chronic pain on analgesic tolerance to morphine is mediated by KOR rather than delta opioid receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Chronic Disease; Drug Tolerance; Formaldehyde; Male; Mice; Morphine; Naltrexone; Oligonucleotides, Antisense; Pain; Pain Measurement; Pain Threshold; Receptors, Opioid, delta; Receptors, Opioid, kappa; Tail

The influence of both acute and chronic restraint stress on the rewarding properties of morphine (1, 2 or 3 mg/kg i.p.) and the aversive effects of naloxone (0.5 mg/kg i.p. x3 or 1.0 mg/kg i.p.) or bremazocine (0.4 mg/kg i.p.) was investigated. An acute (2 h) but not chronic restraint (2 h daily for 7 days) enhanced the morphine place preference, and elicited a place aversion with a subthreshold dose of bremazocine. This enhancing effect on the reinforcing properties induced by the drugs was prevented by either R(+)-SCH-23390 hydrochloride (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H3-benzazepine, 30 microg/kg i.p.) or (+/-)-sulpiride (60 mg/kg i.p.), 10-20 min prior to the stress session. Naltrexone pretreatment (1 mg/kg i.p.) abolished the stress effect on morphine place preference but not that on bremazocine aversion. Instead, nor-BNI (30 microg/3 microl i.c.v.) abolished the stress's effects on bremazocine aversion, but did not modify those on morphine preference. These results show that: (1) acute stress enhanced the morphine and bremazocine conditioned reinforcing effects meanwhile chronic stress did not modify them; (2) the stimulation of D(1) and D(2) dopamine receptors is necessary for the development of restraint stress-induced sensitization to the conditioned reinforcing effects of drugs; and (3) the stimulation mu/delta- and kappa-opioid receptors seems to be differentially involved.

Topics: Acute Disease; Animals; Behavior, Animal; Benzomorphans; Chronic Disease; Conditioning, Operant; Injections, Intraventricular; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Opioid, kappa; Receptors, Opioid, mu; Stress, Psychological

To establish a reliable animal model of chronic arthritic inflammatory pain, to find the optimal parameters and appropriate intervals of repeated 100 Hz transcutaneous electrical nerve stimulation (TENS) for the treatment of the chronic arthritic pain, and to explore the possible central neurochemical mechanisms.. (1) Injection of water-in-oil type complete Freund's adjuvant into the tibio-tarsal joint of the rat produced a reliable, reproducible monoarthritic model. (2) The interval between 2 sessions of stimulations and the intensity of stimulation were important factors determining the therapeutic effects of repeated 100 Hz TENS on both acute and stable period of monoarthritis. (a) For acute period of monoarthritis, the optimal frequency is twice a week, while in the stable period, once a week seems better. (b) The effects of TENS in three intensities: the weaker stimulation was found to produce better results. (3) In the period from 2 to 9 weeks, the levels of spinal release of SP-ir in the TENS group were lower than the control group. This may constitute one of the possible neuro-chemical mechanisms underlying the therapeutic effects of multiple TENS treatment. (4) In both acute and stable period of adjuvant-induced monoarthritis, intrathecal microinjection of Nor-BNI produced dose-dependent increase of arthritic flexion pain scores (i.e. hyperalgesia), suggesting that spinal dynorphin/kappa system plays a role in suppressing arthritic pain.

Topics: Animals; Arthralgia; Arthritis, Experimental; Chronic Disease; Dynorphins; Naltrexone; Pain Threshold; Rats; Substance P; Transcutaneous Electric Nerve Stimulation

We previously reported that the morphine-induced place preference was attenuated under inflammation produced by the unilateral injection of 2.5 % formalin (50 microl) into the hind paw of rats. In the present study, to elucidate the mechanism of this attenuation, the effects of pretreatment with delta- and kappa-opioid receptor antagonists, naltrindole (NTI) and nor-binaltorphimine (nor-BNI), on the development of the morphine-induced place preference under inflammation were examined in rats. Nor-BNI, but not NTI, eliminated the suppression of the morphine-induced place preference in inflamed groups. These results suggest that endogenous kappa-opioid systems may be activated in the presence of chronic inflammatory nociception; as a result, the development of morphine's rewarding effect may be suppressed under inflammation.

Topics: Animals; Chronic Disease; Conditioning, Psychological; Formaldehyde; Hindlimb; Inflammation; Male; Morphine; Naltrexone; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Reward; Time Factors

The aim of our study was to investigate the effect of intracerebroventricular (i.c.v.) administration of very low doses of opioid antagonists on the pain threshold, arterial blood pressure and body temperature of spontaneously hypertensive rats (SHR) with chronic pain. We found that low doses of i.c.v. administered naloxone hydrochloride (0.3 microg) or naloxone methiodide (0.4 microg) produce paradoxical hypoalgesia. Similar results were not observed following i.c.v. administration of nor-binaltorphimine (0.6 microg). A paradoxical increase in the severity of hypertension followed i.c.v. opioid antagonist administration. This suggests an involvement of the opioid system in the mechanisms of blood pressure control. The paradoxical results obtained both for pain threshold and blood pressure after low doses of some opioid antagonists seem to confirm the role played by opioid autoreceptors in these effects. Existence of autoreceptors is suggested. Results obtained following i.c.v. administration of nor-binaltorphimine also suggest a role for the kappa autoreceptor (OP2) in the regulatory mechanisms of thermoregulation.

Topics: Analgesia; Animals; Arteries; Blood Pressure; Body Temperature; Body Weight; Brain; Chronic Disease; Hypertension; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Threshold; Quaternary Ammonium Compounds; Rats; Rats, Inbred SHR; Rats, Inbred WKY

We have previously reported that ischemic spinal cord injury in rats leads to chronic pain-related behaviors. Thus, rats exhibited aversive reactions to innocuous mechanical stimuli (mechanical allodynia) applied to a body area at or rostral to the dermatomes innervated by the injured spinal segments. The responses of the rats to cold are also markedly enhanced (cold allodynia). Interestingly, more than 50% of spinally injured rats did not develop these abnormal pain-related behaviors after spinal cord injury. In the present study, we showed that the extent of injury is similar between allodynic and non-allodynic rats. Furthermore, intrathecal (i.t.) naloxone, a broad-spectrum opioid receptor antagonist, reversibly provoked mechanical and cold allodynia-like responses in spinally injured rats that did not develop such behaviors spontaneously. However, naloxone did not elicit such reactions in normal rats and did not alter the tail-flick latency in normal or spinally injured rats. Furthermore, i.t. D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) or naltridole, selective antagonists of mu and delta opioid receptors, respectively, also triggered pain-related behaviors similarly to naloxone. Although norbinaltorphimine (nor-BIN), a selective kappa-receptor antagonist, also elicited such responses, the time course of the effect makes it unlikely that spinal kappa-receptors were involved. These results suggested that the expression of abnormal pain-related behaviors in some spinally injured rats is tonically suppressed by the spinal opioidergic system. Interindividual differences that lead to lack or dysfunction of such inhibition may underly the appearence of pain-related behavior in some, but not all, spinally injured rats. It is suggested that such inhibition is exerted through spinal mu and delta, but not kappa, opioid receptors. The endogenous opioidergic control appears to be only active against abnormal painrelated behaviors in spinally injured rats. Our results are relevant for the clinical observation that only a subgroup of patients with nerve injury suffers from neuropathic pain.

Topics: Animals; Behavior, Animal; Chronic Disease; Cold Temperature; Female; Hyperalgesia; Injections, Spinal; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Self Mutilation; Somatostatin; Spinal Cord Injuries; Stress, Mechanical