Associative and non-associative mechanisms of morphine analgesic tolerance are neurochemically distinct in the rat spinal cord

Abstract

Opiate tolerance involves both associative and non-associative changes. However, procedures designed to distinguish between these two processes have rarely been employed when investigating the physiological basis of such plasticity. The present experiments assessed some of the mechanisms contributing to both associative and non-associative decreases in morphine analgesic potency following repeated IV morphine administration (4 days, 5 mg/kg per day). For one group of rats, testing for morphine analgesia (tailflick) occurred in a context that had been repeatedly paired with morphine administration. Another group of rats, exposed equally to the testing context, handling procedures and morphine, was tested for morphine analgesia in a context that was specifically unpaired with prior drug. Although both of these groups showed a decrease in the drug effect following repeated administrations, those rats tested in the morphine-associated context were significantly more tolerant than the unpaired group. We evaluated the spinal cord involvement of NMDA receptors, as well as the peptide neurotensin in these two types of tolerance. NMDA receptors appeared to mediate non-associative changes in drug potency, as rats tested in either context were less tolerant when morphine administration was preceded with the non-competitive NMDA antagonist, MK-801 (2.5 and 5 nmol). Spinal neurotensin antagonism with [D-Trp11]neurotensin (3 pmol) selectively abolished associative tolerance. These findings provide information about the mechanisms of opiate tolerance and support the distinction between associative and non-associative processes underlying these changes.

Efficacy of Opioids for Chronic Pain

“…82,117,119 Associative tolerance (which can arise in the case of all the central effects of opioid including euphoria and dysphoria, sedation, analgesia, and nausea) involves learning, and its development is linked to environmental or contextual cues. 132,133 Thus, opioid analgesia can change according to powerful psychologic drivers, learned behaviors, circumstances, and environment. For example, dangerous respiratory depression may arise if habitual heroin users are given equivalent opioid doses to treat acute surgical pain; the different circumstance produces a different level of tolerance.…”

Tolerance and Withdrawal From Prolonged Opioid Use in Critically Ill Children

“…42,88 Changes in these protein-kinase systems and downstream receptor functions occur in supraspinal areas including the forebrain, striatum, thalamus, and brainstem, 89–91 as well as in the spinal cord dorsal horn, 73,74 dorsal root ganglia, and peripheral nociceptors. 55,63,77,82,92,93 Prolonged opioid exposure also activates the expression of antiopioid peptides including vasopressin, oxytocin, neuropeptide FF, cholecystokinin, or nociceptin, and mainly occurs in the spinal cord and brainstem. 94–98 …”

NMDA Antagonists and Tolerance to Drugs Affecting the Central Nervous System

“…Additional support for these results came from studies showing that MK-801 inhibited tolerance in a preparation devoid of supraspinal input (32,106). Moreover, the associative and non-associative forms of tolerance appear to be differentially mediated at the level of the spinal cord, and the NMDA system plays a role in the expression of non-associative tolerance to analgesic effect of morphine (29). It is also noteworthy that the non-competitive NMDA antagonist MK-801, administered 1 h after a stressful stimulus, blocked the development of tolerance to stress-induced analgesia in mice submitted to the hot plate test (111).…”