Antagonism ofN-Methyl-d-aspartate Receptors Reduces the Vulnerability of the Immune System to Stress after Chronic Morphine

Abstract

It has been shown that morphine-tolerant animals have an altered immunological sensitivity to stress. Although the glutamatergic system has been implicated in the neuroadaptive process underlying this tolerant state, its potential role in development of the altered immunological sensitivity consequent to chronic morphine treatment is not known. To determine this, a morphine-tolerant state was induced by 10-day administration of an escalating dose of morphine from 10 to 40 mg/kg (s.c., b.i.d.), and lymphocyte proliferative response to a T-cell mitogen was measured. Morphine challenge (10 mg/kg s.c.) after days of treatment was gradually less immunosuppressive, and this tolerance progression was delayed by concurrent administration of the N-methyl-D-aspartate (NMDA) receptor antagonist (Ϫ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (0.1 mg/kg s.c.) with chronic morphine. The effect was independent of glucocorticoid level changes and was not a result of an acute interaction of the drugs or the prolonged presence of the antagonist alone. Subsequent to chronic treatment, animals were subjected to opioid withdrawal and water stress. Both stressors induced 50% immunosuppression in morphine-tolerant animals compared with saline-treated controls. Increased immunological sensitivity to these stressors was attenuated when MK-801 was administered with chronic morphine as demonstrated by an accelerated recovery rate and lack of immunosuppression from opioid withdrawal and water stress, respectively. Together, these findings provide the first evidence that the neuroadapted state of the immune response after chronic morphine can be modified by NMDA receptor antagonism, as illustrated by a temporal deceleration of the development of immunological tolerance during chronic treatment that is associated with an attenuation of the immunological vulnerability of morphine-tolerant animals to stress.

Methylenedioxymethamphetamine (MDMA, ‘Ecstasy’): a stressor on the immune system

“…Over the last two decades, investigators have documented the ability of a number of drugs of abuse, such as cocaine, opioids, cannabinoids and amphetamines, to impair many aspects of immune function, either directly, or via neuroimmune pathways 1–6 . In addition, there is substantial evidence that the stress associated with morphine and cocaine withdrawal also induces an immunosuppressive state 7,8 . Moreover, numerous reports in a number of experimental models indicate that the immunosuppression elicited by drugs of abuse can result in diminished host resistance to disease 9–12 .…”

Opioid Dependence and NMDA Receptors

“…Furthermore, the literature indicates that blockade of NMDA receptors inhibits many of the diverse symptoms of opioid withdrawal: blood pressure elevation (Buccafusco et al 1995), diarrhea (Ninan and Kulkarni 2000), immunosuppression (Alonzo and Bayer 2003), hyperalgesia (Dunbar and Yaksh 1996), escape behavior (e.g., jumping; Trujillo and Akil 1991), fear and anxiety (Harris et al 2008), and social aggression (Sukhotina and Bespalov 2000).…”