Resting and evoked spinal substance P release during chronic intrathecal morphine infusion: parallels with tolerance and dependence.

Spinal opiate analgesia is associated with presynaptic inhibition of release of excitatory neurotransmitters/neuromodulators, e.g., substance P (SP), from primary afferent terminals. Chronic intrathecal (i.t.) administration of opiates such as morphine results in an initial analgesia followed by tolerance and a state of dependence. In this study, we examined the resting and evoked neurokinin 1 receptor (NK1r) internalization, indicative of endogenous SP release, in dorsal horn neurons of the lumbar spinal cord by immunocytochemistry during chronic i.t. infusion of morphine in rats. Noxious mechanical stimulation (compression) applied to unilateral hind paw evoked a significant increase in NK1r internalization in lamina I neurons in the ipsilateral dorsal horn. Intrathecal morphine infusion (40 nmol/microl/h) for 1 day possessed similar analgesic efficacy as acute morphine and blocked compression-induced spinal NK1r internalization. After 5 days of morphine infusion, thermal escape latencies were the same as in preinfusion animals or saline-infused controls, and compression-evoked NK1r internalization was no longer suppressed. Systemic administration of naloxone to rats on day 6 of morphine infusion resulted in prominent withdrawal behaviors and a concomitant increase in NK1r internalization in dorsal horn. The naloxone-induced internalization was blocked by NK1r antagonist L-703,606 [cis-2-(diphenylmethyl)-N-[(2-iodophenyl)methyl]-1 azabicyclo[2.2.2]octan-3-amine] or pretreatment with capsaicin, confirming that the internalization is due to the endogenous SP release from the primary afferents. We conclude that inability to suppress release of excitatory neurotransmitters/neuromodulators from primary afferents by morphine after chronic exposure is an important component in spinal morphine tolerance, and excessive release from these afferents contributes to the spinal morphine withdrawal syndrome.