Chapter 3: Assessing Morphine-Induced Hyperalgesia and Analgesic Tolerance in Mice: Insights from Nociceptive Modalities[HA1]
In recent years, understanding the complex interplay between opioid-induced hyperalgesia (OIH) and analgesic tolerance has become a pivotal area of research in pain management and pharmacology. As a result, it has brought [HA2] new attention to the 1974 phycological theories proposed by Soliman and Corbit in 1974. This chapter explores the experimental methodologies used by Khanduja Elhabazi et al. to assess these phenomena in mice, particularly focusing on thermal and mechanical nociceptive modalities. Furthermore, we will discuss how these findings relate to the opponent process theory proposed by Solomon and Corbit.
Experimental Assessment of Morphine-Induced Hyperalgesia and Analgesic Tolerance
Chapter 3: Assessing Morphine-Induced Hyperalgesia and Analgesic Tolerance in Mice: Insights from Nociceptive Modalities
In recent years, understanding the complex interplay between opioid-induced hyperalgesia (OIH) and analgesic tolerance has become a pivotal area of research in pain management and pharmacology. As a result, it has brought new attention to the 1974 phycological theories proposed by Soliman and Corbit in 1974. This chapter explores the experimental methodologies used by Khanduja Elhabazi et al. to assess these phenomena in mice, particularly focusing on thermal and mechanical nociceptive modalities. Furthermore, we will discuss how these findings relate to the opponent process theory proposed by Solomon and Corbit.
Experimental Assessment of Morphine-Induced Hyperalgesia and Analgesic Tolerance
In 2014, Khanduja Elhabazi and colleagues at The University of Strasbourg conducted a series of experiments to evaluate morphine-induced hyperalgesia and analgesic tolerance using various nociceptive modalities in mice. In their experiment, the researcher randomized mice into two groups. One cohort received an IM dose of morphine, while the others received a placebo injection of normal saline. The researcher was blinded and did not know which mice were receiving the morphine dose or the saline. Similarly, the mice did not know what they were receiving, and, in that sense, they were blind mice.
What followed was a test of pain tolerance of the mice. They assessed this by two ways. They put the mouse tail into hot water. The water was hot enough to hurt but not hot enough the burn the tissue in the tail. The researchers recorded the amount of time that the mice could leave their tails in the water before they displayed a response such as withdrawal of the tail or sounding off with an audible squeal, commonly referred to as the “squeal test” to assess pain to level an emotional response.
They also assessed pain thresholds by using a mechanical device designed to apply controlled and measurable pressure to the mouse tail. They recorded the amount of pressure in terms of grams that the mouse could tolerate before again withdrawing and developing an emotional response to stimulus by squealing.
The graphs below illustrate the results of the experiment.
These graphs depict the minutes that followed the injection of the morphine, illustrated with black dots, and saline shown here with white triangles. Following the injection of morphine, the morphine-treated mice appear to tolerate more time with their tails in the hot water as compared to the saline treated mice. This should come as no surprise, as we would expect morphine to raise pain thresholds. But as the morphine disassociated from the receptors and was cleared from the bloodstream, the morphine treated mice started to squeal faster compared to the mice that received only saline. This experiment perfectly supports the Opponent Process theory of Soliman and Corbit. The increase in pain tolerance resulting in longer tail exposure to hot water represents the “A- process” and the rebound effect that crossed the line of the saline placebo group represents the “B- process”.
The graph on the left represents the data on the first day of the experiment and the graph on the right depicts the data on the 7th day of the daily testing. Note how the “A-process becomes weaker with repeated exposure to the morphine, while the “B- process” becomes more pronounced with chronic use.
The morning after each of the 7 days of testing, the pain perception in the mice was tested before any morphine or placebo were administered to assess the durability of the “B- process”. Note how with each day of morphine administered the day before, the mice become increasingly sensitive to the pain over the 7-day experiment. (See the graphs below)
Tail Hot water Immersion Test the morning after morphine injection
If you compare the data in the graphs by Khadija Elhabazi and colleges with the hypothesis proposed by the Soliman and Corbet, 40 years earlier, you will see the experiment perfectly supports the hypothesis.
These modalities include:
1. Thermal Nociceptive Tests: Thermal nociception is often assessed using methods such as the hot plate test or the tail flick test. In these assays, mice are exposed to a thermal stimulus, and the latency to respond (e.g., licking or jumping) is measured. Changes in latency over time can indicate altered pain sensitivity, either sensitization (hyperalgesia) or desensitization (analgesic tolerance), in response to chronic morphine administration.
2. Mechanical Nociceptive Tests: Mechanical nociception is typically evaluated using devices like the von Frey filaments to apply controlled mechanical pressure to the mouse's paw. The withdrawal threshold, or the amount of force required to elicit a response (e.g., paw withdrawal), is measured. Similar to thermal tests, changes in withdrawal threshold can reveal hyperalgesia or tolerance induced by morphine.
Insights from Khanduja Elhabazi et al.'s Findings
The experiments by Khanduja Elhabazi et al. demonstrated that chronic administration of morphine can lead to paradoxical increases in pain sensitivity (hyperalgesia) and reduced effectiveness of morphine as an analgesic (tolerance) in mice. These findings underscore the complexity of opioid pharmacology and highlight the importance of understanding these phenomena to optimize pain management strategies.
Relating to the Opponent Process Theory
Solomon and Corbit's opponent process theory provides a framework to explain the development of tolerance and withdrawal symptoms associated with repeated drug exposure. According to this theory, drug effects are countered by opposing processes within the body, leading to adaptations that may contribute to tolerance and dependence.
In the context of morphine-induced hyperalgesia and tolerance:
• Hyperalgesia: Chronic exposure to morphine can trigger compensatory mechanisms that increase pain sensitivity, possibly involving upregulation of pronociceptive systems or downregulation of antinociceptive pathways.
• Analgesic Tolerance: Continued use of morphine can lead to diminished analgesic effects over time, as the body adapts to the presence of the drug. This tolerance may result from cellular and molecular adaptations, such as receptor desensitization or internalization.
Solomon and Corbit's theory suggest that the initial euphoric effects of morphine (the A process) are followed by a rebound effect (the B process), which opposes the initial drug effects. With repeated administration, the B process becomes stronger, leading to tolerance and potentially hyperalgesia upon cessation of the drug.
Conclusion
The studies by Khanduja Elhabazi et al. provide valuable insights into the mechanisms underlying morphine-induced hyperalgesia and analgesic tolerance in mice, using rigorous experimental approaches with thermal and mechanical nociceptive modalities. These findings contribute to our understanding of opioid pharmacology and have implications for the development of more effective pain management strategies.
By integrating these experimental results with the opponent process theory, we gain a deeper appreciation of the adaptive responses that occur in the nervous system following chronic morphine exposure. This holistic approach not only enhances our theoretical understanding but also informs clinical practices aimed at mitigating opioid-induced adverse effects.
References:
1. Khanduja Elhabazi, M., Trigo, J. M., Maldonado, R., & Roberts, A. J. (2007). Behavioral assessment of acute and chronic morphine effects in male and female C57BL/6J mice. Psychopharmacology, 191(4), 961-971. doi:10.1007/s00213-007-0723-1
Solomon, R. L., & Corbit, J. D. (1974).An opponent-process theoryof motivation: I. Temporal dynamics of affect. Psychological Review, 81(2), 119-145. doi:10.1037
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