Antinociceptive tolerance to NSAIDs in the agranular insular cortex is mediated by opioid mechanism

Abstract

Several lines of investigations have shown that in some brain areas, in particular, in the midbrain periaqueductal gray matter, rostral ventromedial medulla, central nucleus of amygdala, nucleus raphe magnus, and dorsal hippocampus, microinjections of nonsteroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. The agranular insular cortex (AIC) is a small region of the cerebral cortex located on the lateral area of the rat's cerebral hemisphere that is involved in the perception and response to pain. In the present study, we investigated the development of tolerance to the analgesic effects of NSAIDs diclofenac, ketorolac, and xefocam microinjected into the AIC in rats. Male Wistar rats receiving NSAIDs into the AIC were tested for antinociception by tail-flick and hot plate tests. Treatment with each NSAID significantly enhanced the tail-flick and hot plate latencies on the first day, followed by a progressive decrease in the analgesic effect over a 4-day period, ie, they developed tolerance. Pretreatment with an opioid antagonist naloxone completely prevented, and posttreatment naloxone abolished, the analgesic effects of the three NSAIDs in both behavioral assays. These findings support the notion that the development of tolerance to the antinociceptive effects of NSAIDs is mediated via an endogenous opioid system possibly involving descending pain modulatory systems.

Keywords: antinociception; descending modulation; endogenous opioids; nociception; non-opioid tolerance.

Figure 1

Serial coronal sections of the rat brain showing placement of microinjections in the AIC (black arrows). Notes: The number below each section represents millimeters relative to bregma. Adapted from the Stereotaxic atlas in Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. Compact third edition. San Diego, CA: Academic Press; 1997. Copyright © 1997 by George Paxinos and Charles Watson. Abbreviation: AIC, agranular insular cortex.

Figure 2

Microinjections of NSAIDs into the AIC for 4 consecutive days. Notes: (A) A progressive decrease in TF latency as compared to intact control group; (B) a progressive decrease in HP latency to intact control group. Statistical analysis was performed by repeated-measure ANOVA with post hoc Tukey–Kramer’s multiple comparisons test; n=6 per test group; **P<0.01, ***P<0.001. Abbreviations: AIC, agranular insular cortex; ANOVA, analysis of variance; HP, hot plate; NSAIDs, nonsteroidal anti-inflammatory drugs; TF, tail-flick.

Figure 3

Pretreatment with naloxone (0.2 μg/0.5 μL) before microinjections of NSAIDs into the AIC. Notes: (A, C and E) Naloxone prevents NSAID-induced antinociception in TF latency for diclofenac (A), ketorolac (C), and xefocam (E), respectively. (B, D and F) Naloxone prevents NSAID-induced antinociception in HP latency for diclofenac (B), ketorolac (D), and xefocam (F), respectively. Statistical analysis was performed by one-way ANOVA with post hoc Tukey–Kramer’s multiple comparisons test; n=6 per test group. Abbreviations: AIC, agranular insular cortex; ANOVA, analysis of variance HP, hot plate; NSAIDs, nonsteroidal anti-inflammatory drugs; TF, tail-flick.

Figure 4

Posttreatment with naloxone (0.2 μg/0.5 μL) after microinjections of NSAIDs into the AIC. Notes: (A, C and E) Naloxone abolishes NSAID-induced antinociception in TF latency for diclofenac (A), ketorolac (C), and xefocam (D), respectively. (B, D and F) Naloxone abolishes NSAID-induced antinociception in HP latency for diclofenac (B), ketorolac (D), and xefocam (F), respectively. Each NSAID-injected group shows significant difference vs saline control and vs naloxone posttreated groups in both tests. Statistical analysis was performed by one-way ANOVA with post hoc Tukey–Kramer’s multiple comparisons test; n=6 per test group. ***P<0.001. Abbreviations: AIC, agranular insular cortex; ANOVA, analysis of variance HP, hot plate; NSAIDs, nonsteroidal anti-inflammatory drugs; TF, tail-flick.