AINEs BLOQUEA TOLERANCIA ANALGESICA. In the tailflick and paw pressure tests. co-administration of ketorolac (30 and 45 micrograms) or S(+) ibuprofen (10 micrograms) with morphine (15 micrograms) prevented the decline of antinociceptive effect and increase in ED50 value. In animals already tolerant to intrathecal morphine, subsequent administration of ketorolac (30 micrograms) with morphine (15 micrograms) partially restored the antinociceptive effect and ED50 value of acute morphine, reflecting the reversal of tolerance.

INTERACCIÓN PSEUDOCRONICA (HIPERSENSIBILIDAD AGUDA) Short-term exposure to a large dose of fentanyl results in delayed hypersensitivity to mechanical stimuli in rats. This hypersensitivity is blocked by intrathecal injection of the COX-1 preferring inhibitor, ketorolac. EFECTO DE OPIOIDES EN COX1 Y 2: Acute fentanyl exposure was not associated with an increase in number of COX-1 or COX-2 expressing ele- ments in the spinal cord. RELEVANCIA CLÍNICA: These data suggest that intrathecal ketorolac, currently in clinical trials under Food and Drug Administration regulation, may transiently reduce the pain-enhancing effects occurring after large doses of opioids are administered, such as during surgery.

VER DEBAJO: AINES REDUCEN ABSTINENCIA. Arachidonic acid and its metabolites (prostaglandins) are involved in the development of opioid withdrawal induced by selective mu opioid agonists: mepacrine (a phospholipase A2 inhibitor), tolmetin (a selective cyclooxygenase-l inhibitor) and meloxicam (a selective cyclooxygenase-2 inhibitor) treatment before or after DAMGO were able to both prevent and reverse the naloxone-induced contraction after exposure to the opioid agonists, in a concentration-dependent fashion.

BLOQUEO POR AINES DE TOLERANCIA ANTINOCICEPTIVA A MORFINA. Antinociceptive (tail-flick test as rat spinal model) tolerance induced by morphine (50 micrograms intrathecally twice daily for 5 days) . NS-398 (selective COX2 inhibitor) and indomethacin (non-selective COX inhibitor), 10 min before each morphine injection, shifted the morphine antinociceptive dose-response curve three- to four-fold to the left when coadministered with morphine during tolerance induction .

Neither NS-398 nor indomethacin alone produced an antinociception effect at doses up to 40 micrograms. NS-398 and indomethacin did not enhance the antinociceptive effect of morphine in naïve and morphine-tolerant rats.

REVIEW ON arachidonic acid metabolites AND OTHER TARGETS IN OPIATE WITHDRAWAL: Dunbar et al. [101] have
demonstrated that acute intrathecal ibuprofen, a selective COX-1 inhibitor, attenuates the hyperalgesia
associated with morphine withdrawal. Moreover, it has been reported that a number of withdrawal signs, encompassing the sensory, autonomic, and motor components of the opioid withdrawal
syndrome, can be partially suppressed by
intrathecal administration of COX-2 selective inhibitors, nimesulide and DuP-697 [89] --> proposed: an adaptive increase in the expression or activity of COX-2 in response to chronic opioid treatment may contribute to the genesis of dependence.. ZALANTZA: there is evidence implicating the activity of arachidonate metabolites generated from the lipoxygenase
[102, 104-106] and
endocannabinoid [107-109] pathways in the induction and expression of opioid dependence.

IN VITRO EN SISTEMA PERIFERICO, ABSTINENCIA REDUCIDA POR AINES: cyclo-oxygenase inhibitors, indomethacin (1.3 microM), mefenamic acid (10 microM), tolmetin (1-10 microM; selective cyclooxygenase-1 inhibitor) and meloxicam (1-10 microM, selective cyclooxygenase-2 inhibitor treatment) reduce the naloxone-precipitated withdrawal contracture of the morphine-dependent guinea-pig ileum in vitro, which are reversed by the concurrent application of a low dose of prosta- glandin E1 (10 nM).

MODULACION DE COX-2 Y PGE2 POR ABSTINENCIA A OPIACEOS:
Spinal prostaglandin E2 release is unaffected by chronic morphine treatment. However, prostaglandin E2 release and COX-2 expression are increased during withdrawal.

EFECTO DE AINES ES MÁS EFICAZ TRAS TTO CRONICO DE MORFINA QUE EN CONTROL: Rats were treated with morphine-containing drinking water for 21 days, which induced morphine dependence. The antinociceptive effects of 8, 16, and 32 mg/kg doses of diclofenac were then evaluated and compared with distilled water in a formalin-based model of pain. Diclofenac potentiated pain suppression in morphine-dependent rats during the inflammation phase of the formalin test and reduced the pain score. In contrast, the antinociceptive effects of diclofenac on morphine-naïve rats was much smaller observed during the inflammation phase.

REVIEW AN HYPOTHESIS ON THE ROLE OF COX IN OPIOID TOLERANCE, HYPERALGESIA AND DEPENDENCE: Overactivity in cyclo-oxygenase pathways and production of prosta-glandins due to long-term exposures of opioid have a critical role in the development of tolerance to antinociceptive effect of opioid, hyperalgesia, and opioid dependence. PROPOSAL: through blending a non-steroid antiinflammatory drug with opioid actively causes reduction in unwanted effects of opioid i.e. by inhibition of opioid-induced cyclo-oxygenase overactivity whereas it is well-known that the combination therapy via reducing opioid dosage reduces the unwanted effects.

INTRODUCTION ON COX AND OPIATE: Chronic and repeated administration of morphine and related
opioid drugs develop tolerance to the antinociceptive effect of opi- oids [16,19,24]. This phenomenon manifests itself in the form of progressive reduction of analgesic potency of opioids. However, in order to achieve desirable analgesic effect in opioid tolerant pa- tients, it is necessary to increasingly escalate opioid dosage [26,27]. This can cause exacerbation of other opioid adverse effects [25]. Thus development of opioid tolerance is a remarkable complica- tion in sustained or high-dose administration of opioids for clinical pain treatment [28]. Prolonged opioid exposure through reduction in opioid receptors density and also desensitization of these receptors lead to induction of adaptive neuroplastic changes in pro-nociceptive and descending analgesic pathways which result in opioid tolerance phenomenon [19,29–33]. Even rat offspring exposed to opioids before birth have shown tolerance to analgesic effect of morphine when they grow up [34,35]. Themechanisms,whichare