Blockade of Striatal Neurone Responses to Morphine by Aminophylline: Evidence for Adenosine Mediation of Opiate Action

Abstract

I The responses of cortical and striatal neurones to morphine and adenosine applied iontophoretically have been studied in the male rat.2 The majority of cells (57%) within the corpus striatum were profoundly inhibited, and a smaller proportion (18%) excited by morphine. Adenosine depressed the firing rate of 30/44 cells in the striatum, excitation never being observed. In contrast, the responses of cortical cells to morphine were typically weak and required longer ejection pulses to effect comparable changes in firing rate. 3 Aminophylline applied iontophoretically, as an anion, proved able to antagonize reversibly both morphine and adenosine in parallel. 4 On a number of cells, y-aminobutyric acid (GABA) was used as a control depressant but aminophylline did not appear to reduce these responses. 5 The responses to morphine (both inhibitory and excitatory) were not easily antagonized by naloxone. Typically, excitatory responses were easier to antagonize than the inhibitory ones. 6 It is concluded that a consequence of the interaction of morphine with its receptors may be the release of adenosine which subsequently produces the inhibition observed with morphine.

The Effects of Morphine and Methionine‐enkephalin on the Release of Purines From Cerebral Cortex Slices of Rats and Mice

“…The previous functional studies which have led to the idea that some effects of morphine may involve an initial release of adenosine have been based upon electrical activity, either resulting from artificial stimulation (Gintzler & Musacchio, 1975;Sawynok & Jhamandas, 1976) or from spontaneous activity (Perkins & Stone, 1980b) so that the enhancement by morphine of electrically induced release from tissues is at least consistent with the earlier work. The previously noted enhancement of veratridine-mediated release (Fredholm & Vernet, 1978) and the present increase of ouabain-induced release from rat tissue, support the suggestion that purine release from brain slices involves the influx of Na+ and Ca2+ ions (Hollins & Stone, 1980b), the movement of which is of course physiologically coupled by the action potential mechanisms.…”

“…These results are at variance with the work of Jhamandas & Dumbrille (1980), but in the latter work, glutamate was used routinely as the releasing stimulus. As morphine has been shown on a number of occasions to reduce glutamate depolarization directly, as the authors themselves note (also Perkins & Stone 1980b) the failure of morphine to enhance glutamate-evoked purine release is less surprising.…”

Theophylline Inhibition of Renal and Cerebral Nucleoside Formation

“…In certain neurones an adenosine-like effect of morphine has recently been demonstrated, and aminophylline antagonized this effect (Perkins & Stone, 1980 …”

Theophylline Does Not Affect Morphine Inhibition of the Isolated Vas Deferens

“…It has also been reported that morphine will enhance release of adenosine from slices or synaptosomes prepared from central tissue (Fredholm & Vernet, 1978;Stone, unpublished observations) and that methylxanthines can block the depressant effects of morphine on neuronal firing (Perkins & Stone, 1980;Stone, 1981).…”

“…The suggestion was made that the inhibitory effects of morphine in this system might involve the initial release of adenosine which would be the agent responsible for the suppression of transmitter release. A number of subsequent studies have investigated this possibility in the central nervous system, with the demonstration that morphine enhances adenosine release from central nervous tissue (Fredholm & Vernet, 1978;Phillis, Jiang, Chelack & Wu, 1979) and that morphine's effects on transmitter release (Jhamandas et al, 1978) and neuronal firing (Perkins & Stone, 1980) can be blocked by methylxanthines.…”