The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity (OIH) and analgesic tolerance. Among the different forms of OIH and tolerance, the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved. Here we demonstrated that the loss of peripheral μ-opioid receptors (MORs) or MOR-expressing neurons attenuated thermal tolerance, but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance. To confirm this result, we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons. Consistent with the behavioral results, peripheral MOR loss did not prevent the opening of Aβ mechanical allodynia pathways in the spinal dorsal horn. Therefore, the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance. Future studies should focus more on central mechanisms.
Humans ; Morphine/pharmacology* ; Hyperalgesia/metabolism* ; Analgesics, Opioid/pharmacology* ; Neurons/metabolism* ; Signal Transduction

Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D₃ receptor (D₃R) have effects on addiction in different animal models. We have previously reported that YQA14, a D₃R antagonist, exhibits very high affinity and selectivity for D₃Rs over D₂Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D₃R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.
Rats ; Mice ; Animals ; Analgesics, Opioid ; Dopamine ; Heroin/pharmacology* ; Dopamine Antagonists/pharmacology* ; Receptors, Dopamine D3/metabolism* ; Morphine/pharmacology* ; Behavior, Addictive/drug therapy* ; Self Administration

Microglia are important cells involved in the regulation of neuropathic pain (NPP) and morphine tolerance. Information on their plasticity and polarity has been elucidated after determining their physiological structure, but there is still much to learn about the role of this type of cell in NPP and morphine tolerance. Microglia mediate multiple functions in health and disease by controlling damage in the central nervous system (CNS) and endogenous immune responses to disease. Microglial activation can result in altered opioid system activity, and NPP is characterized by resistance to morphine. Here we investigate the regulatory mechanisms of microglia and review the potential of microglial inhibitors for modulating NPP and morphine tolerance. Targeted inhibition of glial activation is a clinically promising approach to the treatment of NPP and the prevention of morphine tolerance. Finally, we suggest directions for future research on microglial inhibitors.
Humans ; Calcitonin Gene-Related Peptide/antagonists & inhibitors* ; Drug Tolerance ; Hypoglycemic Agents/pharmacology* ; Microglia/physiology* ; MicroRNAs/physiology* ; Minocycline/pharmacology* ; Morphine/pharmacology* ; Neuralgia/etiology* ; Plant Extracts/pharmacology* ; Signal Transduction/physiology*

Rodent MrgC receptor (Mas-related G-protein-coupled receptor subtype C) shares 65% sequence homology and similarities in terms of expression pattern and binding profile with human Mas-related gene X receptor 1 (hMrgX1). Therefore, researchers generally explore the role of hMrgX1 by studying the function of MrgC receptor. Murine MrgC receptor is uniquely expressed in small-diameter neurons of dorsal root ganglia (DRG) and trigeminal ganglia (TG), which is closely related to the transmission process of pain. This review summarizes the analgesic effects of intrathecal activation of MrgC receptors in pathological pain and morphine tolerance.
Animals ; Drug Tolerance ; Ganglia, Spinal ; Humans ; Mice ; Morphine ; pharmacology ; Pain ; Peptide Fragments ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled ; physiology ; Trigeminal Ganglion

Analgesics, Opioid ; chemistry ; pharmacology ; Animals ; Cattle ; Diazepam ; chemistry ; pharmacology ; Diazepam Binding Inhibitor ; chemical synthesis ; chemistry ; pharmacology ; Dose-Response Relationship, Drug ; Mice ; Morphine ; chemistry ; pharmacology ; Receptors, GABA-A ; metabolism ; Swine

OBJECTIVETo investigate the changes of telemetry electrical activity in the infralimbic cortex (IL) of morphine-dependent rats with extinguished drug-seeking behavior.

METHODSSD rats were randomly divided into model group and control group and received operations of brain stereotaxic electrode embedding in the IL. The rats in the model group were induced to acquire morphine dependence and then received subsequent extinction training, and the changes of electrical activity in the IL were recorded with a physical wireless telemetry system.

RESULTSIn rats with morphine dependence, the time staying in the white box was significantly longer on days 1 and 2 after withdrawal than that before morphine injection and that of the control rats, but was obviously reduced on days 1 and 2 after extinction training to the control level. Compared with the control group, the morphine-dependent rats on day 2 following withdrawal showed significantly increased β wave and decreased δ wave when they stayed in the white box but significantly increased δ wave and decreased α wave and β wave when they shuttled from the black to the white box. On day 2 of extinction, the model rats, when staying in the white box, showed significantly decreased θ wave compared with that of the control rats group but decreased β wave and θ wave and increased δ wave compared with those in the withdrawal period. When they shuttled from black to white box, the model rats showed decreased δ wave and increased α wave and β wave compared with those in the withdrawal period.

CONCLUSIONMorphine-dependent rats have abnormal changes of electrical activity in the IL in drug-seeking extinction to affect their drug-seeking motive and inhibit the expression and maintenance of drug-seeking behaviors.

Animals ; Cerebral Cortex ; drug effects ; physiology ; Drug-Seeking Behavior ; physiology ; Electrophysiological Phenomena ; Extinction, Psychological ; Morphine ; pharmacology ; Morphine Dependence ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Telemetry

The increase of pronociceptive mediators in the dorsal root ganglia (DRG) and spinal dorsal horn is an important mechanism in the pathogenesis of inflammatory pain and opioid tolerance. Adrenomedullin (AM) belongs to calcitonin gene-related peptide (CGRP) family and has been recently demonstrated to be a pain-related peptide. It has also been shown that the expression and release of AM are increased in the DRG and spinal dorsal horn during inflammation and repeated use of morphine. Intrathecal administration of the selective AM receptor antagonist AM22-52 abolishes inflammatory pain and morphine tolerance, suggesting that enhanced AM receptor signaling in the DRG and spinal dorsal horn contributes to the induction of inflammatory pain and morphine tolerance. The present review highlights the recent developments regarding the involvement of AM in these two disorders. The neurological mechanisms of AM's actions are also discussed.
Adrenomedullin ; pharmacology ; Animals ; Calcitonin Gene-Related Peptide ; Drug Tolerance ; Ganglia, Spinal ; drug effects ; Inflammation ; drug therapy ; metabolism ; Morphine ; pharmacology ; Pain ; drug therapy ; metabolism ; Peptide Fragments ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenomedullin ; metabolism

OBJECTIVETo analyse the relationship between the electrical activity changes of nucleus accumbens (NAc) shell and the drug-seeking behavior by recording NAc shell electrical activity in conditioned place preference (CPP) rats induced by morphine.

METHODSForty SD rats were randomly divided into operation-only control group and the morphine-induced CPP group after stereotaxic electrode was buried on rats NAc shell and the latter group was used to establish the morphine CPP model(n = 20). A CPP video system combining with the technique of electrical activity wireless telemetry was used in the study. The NAc electrical activity from each group of rats was recorded by wireless telemetry respectively, which included staying in black or white chamber of video box, shuttling between black-white chambers and between white-black chambers. The electrical activity differences were analyzed by the percentage of each wave.

RESULTSWhen the morphine-induced rats staying in black chamber, compared with the operation-only control group, the NAc shell electrical activity showed that the percentage of 0 - 10 Hz was increased(P < 0.05), meanwhile, those of 10 - 20 Hz and 30 - 40 Hz were reduced(P < 0.05, P < 0.01); when the morphine-induced rats staying in white chamber, the NAc shell electrical activity showed that the percentage of 0 - 10 Hz and 30 - 40 Hz were increased(P < 0.05 , P < 0.01) , that of 10 - 20 Hz was reduced(P < 0.05 , P < 0. 01); when the morphine-induced rats in black- white shuttling status, the NAc shell electrical activity showed that the percentage of 0 - 10 Hz was increased(P <0.05, P <0.01), that of 10- 30 Hz was reduced( P <0.05); and in the white-black shuttling status, the electrical activity showed that the percentage of 0 - 10 Hz was reduced(P <0.05), that of 10 - 30 Hz was increased(P < 0.05) ; the electrical activity was further compared between staying status and shuttling status in the morphine-induced CPP group. There was no significant difference of electrical activity between the rats in white-black shuttling status and staying in white chamber. However, when rats in black-white shuttling status, compared with staying in black chamber, the electrical activity showed that the percentage of 0 - 10 Hz and 40 - 50 Hz were increased(P < 0.05), meanwhile, those of 10 - 20 Hz and 30 - 40 Hz were reduced(P <0.05).

CONCLUSIONThe electrical activity changes of NAc shell in morphine-induced CPP rats were different from those of the operation-only control group, and these changes might be associated to the rat's drug-seeking behavior.

Animals ; Conditioning (Psychology) ; Drug-Seeking Behavior ; Morphine ; pharmacology ; Nucleus Accumbens ; drug effects ; physiology ; Rats ; Rats, Sprague-Dawley ; Telemetry

The purpose of the present study is to analyze the relationship between the telemetry electroencephalogram (EEG) changes of the prelimbic (PL) cortex and the drug-seeking behavior of morphine-induced conditioned place preference (CPP) rats by using the wavelet packet extraction and entropy measurement. The recording electrode was stereotactically implanted into the PL cortex of rats. The animals were then divided randomly into operation-only control and morphine-induced CPP groups, respectively. A CPP video system in combination with an EEG wireless telemetry device was used for recording EEG of PL cortex when the rats shuttled between black-white or white-black chambers. The telemetry recorded EEGs were analyzed by wavelet packet extraction, Welch power spectrum estimate, normalized amplitude and Shannon entropy algorithm. The results showed that, compared with operation-only control group, the left PL cortex's EEG of morphine-induced CPP group during black-white chamber shuttling exhibited the following changes: (1) the amplitude of average EEG for each frequency bands extracted by wavelet packet was reduced; (2) the Welch power intensity was increased significantly in 10-50 Hz EEG band (P < 0.01 or P < 0.05); (3) Shannon entropy was increased in β, γ₁, and γ₂waves of the EEG (P < 0.01 or P < 0.05); and (4) the average information entropy was reduced (P < 0.01). The results suggest that above mentioned EEG changes in morphine-induced CPP group rat may be related to animals' drug-seeking motivation and behavior launching.
Animals ; Conditioning (Psychology) ; Drug-Seeking Behavior ; Electroencephalography ; Entropy ; Morphine ; pharmacology ; Prefrontal Cortex ; drug effects ; Rats ; Telemetry ; Wavelet Analysis

Agmatine ; administration & dosage ; pharmacology ; Analgesia ; methods ; Animals ; Injections, Spinal ; Male ; Morphine ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; drug effects