Opioidmediated Antinociception 71 Spinal Antinociception

That the 5-opoid receptors exist on the terminals of primary afferents in the spinal cord strongly suggests that agonists acting at these sites would be effective antinociceptive agents [83,84]. Shock titration tests performed in rats and monkeys demonstrated that 5-opioid agonists produce antinociception when given intrathecally (ITH), even in morphine-tolerant animals [85]. Both DPDPE and DPLPE given ITH produced dose-dependent antinociception after ITH injection in the mouse [86]. Furthermore, 5-mediated antinociception induced by DPDPE or DPLPE were blocked by the selective A-opioid antagonist ICI 174864 [87]. In other studies, ICI 174,864 produced a right-ward shift in the antinociceptive dose-response curve for spinal DPDPE but not morphine, whereas the A-opioid antagonist h FNA blocked morphine but not DPDPE [88]. Inhibition of the tail flick reflex by applying a noxious conditioning stimulus to the hindpaw of the rat was blocked by the spinal injection of h FNA or the 5-opioid antagonist H-Tyr-Tic psi[CH2NH]Phe-Phe-OH, suggesting that endogenous ligands for the a- and 5-opioid receptors are released in response to nociceptive inputs [89]. Further evidence for an endogenous compound acting at the spinal 5-opioid receptor site was indicated when the peptidase inhibitor kelatorphan did not further enhance the ability of the 5-opioid agonist Tyr-D-Ser(Otbu)-Gly-Phe-Leu-Thr (DSTBU-LET) to attenuate dorsal horn unit activity in response to electrical stimulation at C-fiber intensities [90].

In contrast, there was an enhanced response to A-agonists, indicating that separate endogenous substrates act at each of these receptors [90]. The spinal administration of NTI produced a shift to the right of the dose-response curve for DPDPE, but not DAMGO, in the rat tail flick and hot plate tests [91]. Furthermore, apparent pA2 values obtained from these studies provided additional evidence that NTI acts as a selective 5-opioid antagonist in vivo [91]. Similar to ITH bolus injecions, spinal infusions of [D-Ala2,Glu4] deltorphin also produced NTI and naloxone-sensitive antinociception in the rat [92]. Later studies showed that although ICI 174,864 abolished the antinociceptive effect of spinal DPDPE and [D-Ala2,Glu4]deltorphin, DPDPE was blocked by DALCE and not 5-NTII whereas [D-Ala2,Glu4] deltorphin was blocked by 5-NTII and not DALCE [42]. Moreover, neither morphine nor DAMGO was antagonized by these doses, indicating selective antagonistic activity of DALCE and 5-NTII at the 51- and 52- opioid receptors, respectively [42].

In a detailed pharmacological study, it was found that ITH [D-Ala2, Glu4]deltorphin was ~ 10-fold more potent than DPDPE in the rat tail flick test [40]. Naltriben increased the ED50 of [D-Ala2,Glu4]deltorphin 25-fold without altering that of DPDPE [40]. Surprisingly, ITH [D-Ala2,Glu4]deltor-phin did not produce antinociception in the hot plate test at doses that did not also produce motor impairment, whereas DPDPE was effective in the latter test [40]. These results were taken as pharmacological evidence of differential actions of spinal 51- and 52-opioid receptors in the spinal cord. Later studies by the same group also showed the participation of spinal 51-opioid receptors in modulation of nociception [93]. The selective 51-antagonist, 7-benzylide-nenaltrexone (BNTX) blocked the antinociceptive effect of ITH DPDPE in the tail flick and hot plate tests without inhibiting the actions of either [D-Ala2,Glu4]deltorphin or DAMGO [93]. Interestingly, blockade of the 51-opi-oid receptor enhanced the antinociceptive effect of [D-Ala2,Glu4]deltorphin [93]. A different profile was revealed when antinociception was produced by glutamate-induced stimulation of the nucleus raphe magnus (NRM) or the nucleus reticularis gigantocellularis pars alpha (NGCpa) [94]. The ITH injection of BNTX ^antagonist) did not block antinociception elicited by either site, whereas naltriben blocked the antinociception induced by glutamate in the NRM, but not the NGCpa. It was concluded that antinociception mediated through bulbospinal pathways depends on 52-, and not 51-, opioid receptor activation [94,95].

Studies employing endpoints other than tail flick and hot plate have shown antinociceptive activity mediated through spinal 5-opioid receptor sites. Low (i.e., 5-selective) concentrations of DPDPE or morphine inhibited K + -evoked release of substance P from trigeminal slices. Furthermore, this inhibitory effect was blocked by naloxone or ICI 174,864, but not by h-FNA or BNI (6antagonist) or naloxonazine (a1 antagonist) [95]. Mechanical and thermal noxious stimuli evoked the release of substance P measured by microdialysis in the spinal cord, and this action was attenuated by spinal infusions of [Met5]enkephalin [96]. Naltrindole not only blocked the effect of exogenous [Met5]enkephalin, but, when given alone, it elicited a 75% increase in the basal release of substance P-like immunoreactivity, suggesting the presence of an inhibitory tone [96]. Similar observations were made with the 5-opioid agonists Tyr-D-Thr-Gly-Phe-Leu-Thr and dermenkephalin [97]. Behavioral demonstration of an endogenous 5-opioid receptor-mediated inhibitory tone that modulates nociceptive inputs was shown when the ITH administration of naltrindole or of antisera to [Leu5]enkephalin, a putative endogenous 5-opioid agonist, produced marked, significant increases in the tonic phase of formalin-induced flinching in rats [98].

In contrast, neither h-FNA nor antiserum to [Met5]enkephalin enhanced formalin-induced flinching behavior in the same study [98]. In the same study, ITH DPDPE and DAMGO blocked formalin-induced flinching, and these effects were antagonized by naltrindole and h-FNA, respectively [98]. In similar studies, the spinal administration of DPDPE or [D-Ala2,Glu4]deltorphin produced an inhibition of formalin-induced flinching that was blocked by selective antagonists at 51 and 52 receptors, respectively [94]. Surprisingly, DPDPE produced only a moderate inhibition of Fos expression in spinal dorsal horn neurons, and [D-Ala2,Glu4]deltorphin did not produce any suppression of Fos expression [94]. In contrast, DAMGO produced dramatic decreases in flinching behavior and completely prevented Fos expression in response to nociceptive stimulus. It was surmised that the predominant presynaptic site of action of the 5-opioid receptors allowed a sufficient number of postsynaptic second-order neurons to express Fos [94].

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