morphinans and phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide

The decision to perform, or not perform, actions known to lead to a rewarding outcome is strongly influenced by the current incentive value of the reward. Incentive value is largely determined by the affective experience derived during previous consumption of the reward-the process of incentive learning. We trained rats on a two-lever, seeking-taking chain paradigm for sucrose reward, in which responding on the initial seeking lever of the chain was demonstrably controlled by the incentive value of the reward. We found that infusion of the μ-opioid receptor antagonist, CTOP (d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH(2)), into the basolateral amygdala (BLA) during posttraining, noncontingent consumption of sucrose in a novel elevated-hunger state (a positive incentive learning opportunity) blocked the encoding of incentive value information normally used to increase subsequent sucrose-seeking responses. Similar treatment with δ [N, N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864)] or κ [5'-guanidinonaltrindole (GNTI)] antagonists was without effect. Interestingly, none of these drugs affected the ability of the rats to encode a decrease in incentive value resulting from experiencing the sucrose in a novel reduced-hunger state. However, the μ agonist, DAMGO ([d-Ala2, NMe-Phe4, Gly5-ol]-enkephalin), appeared to attenuate this negative incentive learning. These data suggest that upshifts and downshifts in endogenous opioid transmission in the BLA mediate the encoding of positive and negative shifts in incentive value, respectively, through actions at μ-opioid receptors, and provide insight into a mechanism through which opiates may elicit inappropriate desire resulting in their continued intake in the face of diminishing affective experience.

Topics: Amygdala; Animals; Conditioning, Operant; Drive; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Food; Guanidines; Male; Microinjections; Morphinans; Naltrexone; Narcotic Antagonists; Neuropsychological Tests; Rats; Rats, Long-Evans; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reward; Somatostatin; Sucrose

Recently, it has been known that the antinociception of sildenafil, a phosphodiesterase 5 inhibitor, is mediated through the opioid receptors. There are common three types of opioid receptors mu, delta, and kappa. We characterized the role of subtypes of opioid receptor for the antinociception of sildenafil at the spinal level. Intrathecal catheters were placed for drug delivery and formalin solution (5%, 50 microl) was injected for induction of nociception within male SD rats. The effect of mu opioid receptor antagonist (CTOP), delta opioid receptor antagonist (naltrindole), and kappa opioid receptor antagonist (GNTI) on the activity of sildenafil was examined. Intrathecal sildenafil decreased the flinching responses during phases 1 and 2 in the formalin test. Intrathecal CTOP and naltrindole reversed the antinociception of sildenafil during both phases in the formalin test. Intrathecal GNTI reversed the effect of sildenafil during phase 2, but not phase 1. These results suggest that sildenafil is effective to acute pain and the facilitated pain state at the spinal level. Both mu and delta opioid receptors are involved. However, it seems that kappa opioid receptors play in the effect of sildenafil.

Topics: Animals; Behavior, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Guanidines; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pain Measurement; Pain Threshold; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Sildenafil Citrate; Somatostatin; Sulfones; Time Factors

Due to low central nervous system (CNS) bioavailability of delta-opioid peptides, little is known about the effect of systemic administration of delta-opioid receptor ligands. The present study examined the effect of non-peptidergic delta-opioid receptor agonists, (+)-4-[(alphaR)-alpha-((2R,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80) and (-)dibenzoyl-L-tartaric acid salt (SNC86), on the activity of alpha-motoneurons in decerebrate-spinal rats. The flexor reflex was facilitated by C-afferent conditioning inputs, shown by a decrease in mechanical threshold and increase in touch- and pinch-evoked responses. Systemic administration of SNC80 (10 micromol/kg) prevented and reversed the neuronal hyperactivity. We further examined the effect of this agonist on the hypersensitivity of the flexor reflex induced by intraplantar injection of Freund's adjuvant. SNC80 dose-dependently (1, 3, 5 and 10 micromol/kg) increased the mechanical threshold and decreased touch-, pinch- and Abeta-afferent inputs-evoked responses. Similar effects were seen with SNC86 (5 micromol/kg). Pretreatment with either naloxone (20 micromol/kg, i.p.) or (Cyclopropylmethyl)-6,7-dehydro-4,5alpha-epoxy-14beta-ethoxy-5beta-methylindolo [2',3':6',7']morphinan-3-ol hydrochloride (SH378; 5 micromol/kg, intraarterially (i.a.)), a novel selective delta-opioid receptor antagonist, completely abolished the anti-hypersensitivity effect of SNC80. The effect of SNC80 remained following intrathecal administration of mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP; 1.5 nmol). These results indicate that systemic injection of SNC80 exerted antihypersensitivity in models of both acute and tonic nociception and these effects are mediated mainly through a spinal delta-opioid mechanism.

Topics: Afferent Pathways; Animals; Benzamides; Central Nervous System; Conditioning, Psychological; Dose-Response Relationship, Drug; Drug Hypersensitivity; Electric Stimulation; Electrophysiology; Freund's Adjuvant; Hindlimb; Indoles; Inflammation; Male; Morphinans; Motor Neurons; Naloxone; Narcotic Antagonists; Pain Measurement; Piperazines; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Reflex; Somatostatin; Tartrates; Touch

Previous work has demonstrated that 3 pharmacologically and neuroanatomically distinct analgesia systems can be sequentially activated by increasing numbers of transcutaneous tail-shock. To date, the categorization of the early (after 2 tail-shocks) and late (after 80-100 tail-shocks) analgesias as opiate-mediated has been based on the ability of systemic naltrexone and morphine tolerance to block these effects. In contrast, the analgesia observed after 5-40 tail-shocks is unaffected by these manipulations, leading to its categorization as non-opiate. The present work and the following companion paper were aimed at identifying the neuroanatomical loci at which endogenous opiates exert their analgesic effects in this tail-shock paradigm and, further, to identify which opiate receptor subtypes are involved. The 3 experiments included in the present paper focus on the role of spinal opiates in tail-shock induced analgesia. The first experiment demonstrates that the tail-shock parameters used do not directly activate pain suppressive circuitry within the spinal cord, but rather activate centrifugal pain modulation circuitry originating within the brain. The last two experiments examine the effect of intrathecal microinjection of either naltrexone (a relatively non-selective opiate receptor antagonist), binaltorphimine (kappa receptor antagonist), Cys2-Tyr3-Orn5-Pen7-amide (CTOP) (mu receptor antagonist), or naltrindole (delta receptor antagonist). Taken together, these latter 2 experiments demonstrate that both the early (after 2 shocks) and late (after 80-100 shocks) opiate analgesias are mediated by kappa opiate receptors within the spinal cord.

Topics: Analysis of Variance; Animals; Dose-Response Relationship, Drug; Electroshock; Indoles; Injections, Spinal; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pain; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Somatostatin; Spinal Cord

We assessed the effects of antagonists selective for mu (mu), delta (delta) or kappa (kappa) opioid receptors on the induction of long-term potentiation (LTP) and short-term potentiation (STP) at the rat hippocampal mossy fiber-CA3 synapse in vivo. The mu opioid receptor-selective antagonist Cys2,Tyr3,Orn5,Pen7 amide (CTOP, 1 or 3 nmol) did not alter either mossy fiber-CA3 responses evoked at low frequencies or previously potentiated mossy fiber-CA3 responses, but it attenuated the induction of mossy fiber LTP in a dose-dependent manner. By contrast, LTP of CA3 responses evoked by stimulation of commissural afferents to the CA3 region was unaffected by CTOP. Neither the delta opioid receptor-selective antagonist naltrindole hydrochloride (0.3-10 nmol) or the kappa opioid receptor-selective antagonist nor-binaltorphimine hydrochloride (3-10 nmol) altered the induction of mossy fiber LTP. Thus, a role for delta or kappa opioid receptors in the induction of mossy fiber LTP could not be demonstrated. CTOP, in quantities that attenuated mossy fiber LTP induction, also attenuated the magnitude of mossy fiber STP measured 5 sec after delivery of conditioning trains. Further examination of the component of STP corresponding to post-tetanic potentiation (PTP) revealed that CTOP selectively attenuated the estimated magnitude and time constant of decay of mossy fiber PTP. These results suggest that the frequency-dependent activation of mu opioid receptors by endogenous opioid peptides is required for the induction of LTP at hippocampal mossy fiber synapses.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Evoked Potentials; Hippocampus; Indoles; Male; Morphinans; Naltrexone; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Somatostatin; Synapses; Time Factors

Topics: Animals; Binding, Competitive; Brain; Diprenorphine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Guinea Pigs; In Vitro Techniques; Indoles; Morphinans; Naltrexone; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Somatostatin