Spinal amino acid release and precipitated withdrawal in rats chronically infused with spinal morphine

Abstract

Glutamate receptors are implicated in the genesis of opioid tolerance and dependence. Factors governing release of amino acids in systems chronically exposed to opiates, however, remain undefined. Using rats, each prepared with a spinal loop dialysis catheter and with a chronic lumbar intrathecal infusion catheter connected to a subcutaneous minipump, the release of amino acids before and during antagonist-precipitated withdrawal in unanesthetized rats was examined. Spinal infusion of morphine (20 nmol/micro l/hr) for 4 d had little effect on resting release of amino acids. In morphine-infused, but not saline-infused, rats naloxone (2 mg/kg, i.p.) evoked an immediate increase in the release of L-glutamate (299 +/- 143%) and taurine (306 +/- 113%) but not other amino acids. The magnitude and time course of the release of these amino acids significantly correlated with behavioral indices of withdrawal intensity. Acute intrathecal pretreatment immediately before naloxone with clonidine (20 microg; alpha2 agonist), MK-801 (3 microg; noncompetitive NMDA antagonist), or aminophosphonopentanoic acid (AP-5; 3 microg; competitive NMDA antagonist) suppressed naloxone-induced increases in spinal L-glutamate and taurine release and behavioral signs of withdrawal in spinal morphine-infused rats. Results point to a correlated increase in spinal L-glutamate release, which contributes to genesis of the opioid withdrawal syndrome. Agents such as clonidine that suppress opioid withdrawal may owe their action to an inhibition of excitatory amino acid release. The effects of MK-801 and AP-5 suggest a glutamate-evoked glutamate release.

Loss of intrathecal morphine analgesia in terminal cancer patients is associated with high levels of excitatory amino acids in the CSF

“…However, the increase was not significant and the authors suggested that EAA might not play a role in morphine tolerance. 14 This discrepancy between their results and ours might be due to differences between cancer pain patients and naïve rats. Alternatively, only a small amount of EAA released after IT morphine infusion in the study by Jhamanda et al may still have resulted in a reduction of morphine's antinociceptive effect.…”

Morphine Tolerance and Reward but not Expression of Morphine Dependence are Inhibited by the Selective Glutamate Carboxypeptidase II (GCP II, NAALADase) Inhibitor, 2-PMPA

“…If this hypothesis were correct, it could be speculated that administration of a high dose (100 mg/kg) of 2-PMPA leads to high concentrations of NAAG that acts as an agonist, rather than an antagonist at NMDA receptors, and thus increases the severity of morphine withdrawal. In support, it should be noted that during opioid withdrawal there is a massive release of glutamate (Rasmussen, 1995;Jhamandas et al, 1996;Sepulveda et al, 1998). The effects of massive glutamate release apparently may not be prevented by NAAG-induced mGluRII stimulation and/or a decrease in glutamate release.…”

Spinal Matrix Metalloproteinase-9 Contributes to Physical Dependence on Morphine in Mice

“…Adaptive changes following chronic opioid exposure that might underlie physical dependence by altering neuronal excitability and synaptic transmission include a rebound increase in cAMP levels and in expression of certain types of adenylyl cyclase, guanylyl cyclase, PKA, PKG, and cAMP response element binding protein (CREB) (Nestler, 2001;Barrot et al, 2002;ShawLutchman et al, 2002). The regions important in opioid actions include the spinal cord and supraspinal levels (Jhamandas et al, 1996;Bailey and Connor, 2005;Muscoli et al, 2007;Han et al, 2008;Liu et al, 2009a). Despite decades of investigation, the specific cellular and molecular mechanisms underlying opioid actions remain elusive.…”