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

Evidence indicates that periaqueductal gray matter (PAG) plays an important role in defensive responses and pain control. The activation of cannabinoid type-1 (CB1) or mu-opioid (MOR) receptors in the dorsal region of this structure (dPAG) inhibits fear and facilitates antinociception induced by different aversive stimuli. However, it is still unknown whether these two receptors work cooperatively in order to achieve these inhibitory actions. This study investigated the involvement and a likely interplay between CB1 and MOR receptors localized into the dPAG on the regulation of fear-like defensive responses and antinociception (evaluated in tail-flick test) evoked by dPAG chemical stimulation with N-methyl-d-aspartate (NMDA). Before the administration of NMDA, animals were first intra-dPAG injected with the CB1 agonist ACEA (0.5 pmol), or with the MOR agonist DAMGO (0.5 pmol) in combination with the respective antagonists AM251 (CB1 antagonist, 100 pmol) or CTOP (MOR antagonist, 1 nmol). To investigate the interplay between these receptors, microinjection of CTOP was combined with ACEA, or microinjection of AM251 was combined with DAMGO. Our results showed that both the intra-PAG treatments with ACEA or DAMGO inhibited NMDA-induced freezing expression, whereas only the treatment with DAMGO increased antinociception induced with NMDA, which are completely blocked by its respective antagonists. Interestingly, the inhibitory effects of ACEA or DAMGO on freezing was blocked by CTOP and AM251, respectively, indicating a functional interaction between these two receptors in the mediation of defensive behaviors. However, this cooperative interaction was not observed during the NMDA-induced antinociception. Our findings indicate that there is a cooperative action between the MOR and CB1 receptors within the dPAG and it is involved in the mediation of NMDA-induced defensive responses. Additionally, the MORs into the dPAG are involved in the modulation of the antinociceptive effects that follow a fear-like defense-reaction induced by dPAG chemical stimulation with NMDA.

Topics: Analgesics, Opioid; Animals; Arachidonic Acids; Behavior, Animal; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Excitatory Amino Acid Agonists; Fear; Freezing Reaction, Cataleptic; Male; Microinjections; N-Methylaspartate; Nociception; Pain; Pain Measurement; Periaqueductal Gray; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Receptors, Opioid, mu; Somatostatin

Pain sensation is characterized as a complex experience, dependent on sensory processes as well as the activation of limbic brain areas involved in emotion, among them anterior insula. This cortical area is involved in the perception and response to painful stimuli. We investigated if this area contributes to antinociception produced by NSAIDs, and underlying mechanisms. We found that administration of NSAIDs into the anterior insular cortex in rats reduced mechanical and heat hyperalgesia produced by intraplantar injection of formalin, and this was attenuated by pre- or post-treatment with the opioid receptor antagonists, naloxone and CTOP, and the cannabinoid receptor (CB1) antagonist AM-251. These data support the concept that NSAID-evoked antinociception is mediated via descending endogenous opioid and cannabinoid systems inhibiting spinal paw withdrawal reflexes in rodents.

Topics: Analgesia; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cerebral Cortex; Endocannabinoids; Male; Naloxone; Nociception; Opioid Peptides; Piperidines; Pyrazoles; Rats; Rats, Wistar; Somatostatin

Painful stimuli activate nociceptive C fibers and induce synaptic long-term potentiation (LTP) at their spinal terminals. LTP at C-fiber synapses represents a cellular model for pain amplification (hyperalgesia) and for a memory trace of pain. μ-Opioid receptor agonists exert a powerful but reversible depression at C-fiber synapses that renders the continuous application of low opioid doses the gold standard in pain therapy. We discovered that brief application of a high opioid dose reversed various forms of activity-dependent LTP at C-fiber synapses. Depotentiation involved Ca(2+)-dependent signaling and normalization of the phosphorylation state of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This also reversed hyperalgesia in behaving animals. Opioids thus not only temporarily dampen pain but may also erase a spinal memory trace of pain.

Topics: Analgesics, Opioid; Animals; Calcium Signaling; Evoked Potentials; Hyperalgesia; Long-Term Potentiation; Male; Naloxone; Nerve Fibers, Unmyelinated; Nociceptive Pain; Phosphorylation; Piperidines; Protein Kinase C; Protein Phosphatase 1; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Opioid, mu; Remifentanil; Sciatic Nerve; Somatostatin; Spinal Cord; Synapses

Ischemic pre- or post-conditioning of the heart has been shown to involve opioid receptors. Remifentanil, an ultra-short-acting selective mu opioid receptor agonist in clinical use, pre-conditions the rat heart against ischemia-reperfusion injury. This study investigates whether remifentanil post-conditioning is also cardioprotective.. Remifentanil post-conditioning (5-min infusion at 1, 5, 10 or 20 microg/kg/min) or ischemic post-conditioning (three cycles of a 10 s reperfusion interspersed with a 10 s ischemia) was induced in an open-chest rat heart model of ischemia and reperfusion injury, in the presence or absence of nor-binaltorphimine, naltrindole or CTOP, specific kappa, delta and mu opioid receptor antagonists, respectively. The same sequence of experiments was repeated in the isolated heart model using the maximal protective dose of remifentanil from the dose-response studies.. Both ischemic and remifentanil post-conditioning reduced the myocardial infarct size relative to the control group in both models. This cardioprotective effect for both post-conditioning regimes was prevented by the prior administration of nor-binaltorphimine and naltrindole but not CTOP. The sole administration of the antagonists had no effect on the size of myocardial infarction.. These results indicate that remifentanil post-conditioning protects the heart from ischemia-reperfusion injury to a similar extent as of ischemic post-conditioning. This protection involves kappa and delta but not mu opioid receptor activation. This drug has great potential as a clinical post-conditioning modality as it can be given in large doses without prolonged opioid-related side effects.

Topics: Analgesics, Opioid; Animals; Blood Pressure; Cardiotonic Agents; Dose-Response Relationship, Drug; Heart Rate; In Vitro Techniques; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Naltrexone; Narcotic Antagonists; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Remifentanil; Somatostatin