Autoantibodies against opioid or glutamate receptors are associated with changes in morphine reward and physical dependence in mice.
BACKGROUND
Possible interactions between nervous and immune systems during opioid addiction remain elusive. Recombinant mu-delta opioid receptors (MDOR) and the glutamate receptor 1 (GluR1) subunit of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors are involved in acute and chronic effects of morphine. Elevated levels of autoantibodies (aAbs) to these receptors were demonstrated in heroin human addicts and in animal models. This study characterized the role of aAbs to these receptors in behavioral modulations recruited during opioid tolerance and sensitization.


RESULTS
Male CD-1 mice, immunized with either MDOR or GluR1 peptide fragments (80 microg intraperitoneal (i.p.)), were examined for spontaneous behavior and response to morphine (5 mg/kg i.p.). Spontaneous home-cage activity, novelty-induced self-grooming and morphine-induced hyperactivity were higher in GluR1 mice compared to Vehicle subjects, whereas MDOR immunization was associated with an increased morphine-induced conditioned place preference. In response to escalating doses of morphine (from 10 to 60 mg/kg i.p., twice daily) and naloxone-precipitated withdrawal (1 mg/kg subcutaneous), GluR1 mice exhibited a more marked stereotyped sniffing behavior and less body tremors compared to Vehicle subjects, whereas less sniffing and teeth chattering were found in MDOR mice. The expected downregulation of mu receptor binding sites, induced by chronic morphine in vehicle subjects, was completely absent following MDOR immunization.


CONCLUSIONS
These findings indicate an altered response to morphine-related reinforcing and aversive effects in MDOR mice and altered coping with the environment in GluR1 mice. Circulating aAbs to specific neuroreceptors may alter the response to opiates and play a role as determinants of vulnerability to opiate addiction.
Capone
Francesca
F
Section of Behavioral Neuroscience, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, Italy.
Adriani
Walter
W
Shumilina
Maria
M
Izykenova
Galina
G
Granstrem
Oleg
O
Dambinova
Svetlana
S
Laviola
Giovanni
G
D000818:Animals; D001143:Arousal / Q000187:drug effects; D001323:Autoantibodies / Q000097:blood*; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000276:immunology; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006120:Grooming / Q000187:drug effects; D007114:Immunization; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009021:Morphine Dependence / Q000276:immunology*; D009042:Motivation; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D010446:Peptide Fragments / Q000276:immunology; D018091:Receptors, AMPA / Q000276:immunology*; D017465:Receptors, Opioid, delta / Q000276:immunology*; D017450:Receptors, Opioid, mu / Q000276:immunology*; D012201:Reward; D012931:Social Environment; D013239:Stereotyped Behavior / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000276:immunology
D001323:Autoantibodies; D009020:Morphine; D009270:Naloxone; D010446:Peptide Fragments; D018091:Receptors, AMPA; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu