The synergistic effect of concurrent spinal and supraspinal opiate agonisms is reduced by both nociceptive and morphine pretreatment.

The antinociceptive effect of morphine administered into the periaqueductal gray (PAG), the intrathecal space (ITH) and concurrently, into both sites (in a 1:1 dose ratio), was assessed in 1) nontolerant rats, 2) rats made tolerant to the effect of morphine on the tail-flick (TF) test and 3) rats that were tested on the TF during chronic saline administration. In nontolerant rats, concurrent morphine injections produced a multiplicative antinociceptive effect (ED50 = 0.392 microgram, total dose) relative to that obtained after separate PAG (ED50 = 2.8 micrograms) or ITH (ED50 = 6.7 micrograms) injections. The multiplicative effect of concurrent morphine administration was significantly reduced in rats made tolerant to morphine (one 3 mg/kg SC injection and TF test per day for six days). Opiate synergy was also reduced but to a smaller extent in rats that were repeatedly tested on the TF during chronic saline administration (one SC injection and TF test per day for six days). Neither chronic morphine nor saline pretreatment altered the dose-response function to intrathecal morphine. However, both morphine and saline pretreatment significantly reduced the antinociceptive effect of morphine administered into the PAG. The data indicate that concurrent morphine administration into the PAG and ITH space results in a synergistic antinociceptive action which is reduced by performance of the nociceptive response, even in the absence of opiate administration. We suggest that the decrease in opiate synergism produced by nociceptive assessment (behavioral tolerance) is mediated supraspinally, while the additional decline resulting from morphine administered in conjunction with the nociceptive tests (opiate tolerance) is mediated by a combined action at spinal and supraspinal sites.