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

The ascending excitatory reflex is part of the peristaltic reflex, an important participant in intestinal propulsion. The aim of this study was to characterize the role of different opioid receptors in the ascending reflex through exogenous application of non-selective (Met-enkephalin) and selective opioid agonists (mu-PLO17, delta-DPDPE, kappa-U-50, 488) as well as selective opioid receptor antagonists (mu: CTOP-NH(2), delta: ICI-174,864, kappa: Nor-Binaltorphimine). Metenkephalin (IC(50): 0.06 microM) and morphine (IC(50): 1.8 microM) inhibited the ascending reflex response concentration-dependently. Both the mu-selective agonist PLO17 (IC(50): 0.83 microM, n =11) and the kappa-selective agonist U-50,488 (IC(50): 0.68 microM, n =8) concentration-dependently inhibited the magnitude of the ascending contractile reflex response, whereas the delta-agonist DPDPE (10(-10)-10(-6)M) had no significant effect. In contrast, the latency of the response (time interval between start of the stimulus and onset of the contraction) was significantly prolonged by PLO17 > morphine > Met-enkephalin > DPDPE, whereas U-50,488 showed no effect. When the effect of the receptor-specific antagonists was tested, only CTOP-NH(2)and Nor-BNI caused a significant increase of the contractile response, whereas ICI-174 864 was ineffective. On the other hand, CTOP-NH(2)> ICI-174 864 decreased the latency significantly but the kappa-receptor agonist Nor-BNI had no influence. Thus, mu- and kappa-receptors seem to be involved in regulating the contraction strength of the ascending reflex, whereas both mu- and delta-receptors seem to be involved in the timing of the reflex response.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Endorphins; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine; Enkephalin, Methionine; Ileum; In Vitro Techniques; Male; Morphine; Muscle, Smooth; Naltrexone; Narcotic Antagonists; Narcotics; Peristalsis; Rats; Rats, Wistar; Receptors, Opioid; Somatostatin

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