Does modulation of spinal N-methyl-D-aspartic acid receptor by pre-activation accelerate the development of morphine tolerance?

Repeated morphine administration usually leads to a number of neuroadaptive processes, including tolerance and sensitization. However, research has shown that the induction and maintenance of central sensitization is dependent on N-methyl-d-aspartic acid receptor (NMDAR) activation. Chronic morphine exposure has been shown to result in spinal sensitization and activation of spinal NMDARs. Chronic morphine treatment and the activation of spinal NMDARs may be synergistic and form a closed loop that may worsen the development of morphine analgesic tolerance and spinal sensitization. Inhibition of NMDARs with an antagonist could effectively alleviate the development of morphine analgesic tolerance. So, what is the effect of modulating spinal NMDAR activation with exogenous agonists or neuropathic input on the development of morphine-induced analgesic tolerance? Our hypothesis is that chronic morphine treatment may worsen the already activation of spinal NMDARs and spinal sensitization after agonist application or neuropathic input to shorten the process of morphine-induced analgesic tolerance.