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Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation.

Johnson JL, Rolan PE, Johnson ME, Bobrovskaya L, Williams DB, Johnson K, Tuke J, Hutchinson MR - Transl Psychiatry (2014)

Bottom Line: Chronic morphine therapy has been associated with paradoxically increased pain.IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity.Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.

View Article: PubMed Central - PubMed

Affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia.

ABSTRACT
Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. In silico docking simulations indicate codeine also docks to MD2, an accessory protein for TLR4, suggesting potential to induce TLR4-dependent pain facilitation. We hypothesized codeine would cause TLR4-dependent hyperalgesia/allodynia that is disparate from its opioid receptor-dependent analgesic rank potency. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests at days 0, 3 and 5 in mice receiving intraperitoneal equimolar codeine (21 mg kg(-1)), morphine (20 mg kg(-1)) or saline, twice daily. This experiment was repeated in animals with prior partial nerve injury and in TLR4 mutant mice. Interventions with interleukin-1 receptor antagonist (IL-1RA) and glial-attenuating drug ibudilast were assessed. Analyses of glial activation markers (glial fibrillary acid protein and CD11b) in neuronal tissue were conducted at the completion of behavioural testing. Despite providing less acute analgesia (P=0.006), codeine induced similar hotplate hyperalgesia to equimolar morphine vs saline (-9.5 s, P<0.01 and -7.3 s, P<0.01, respectively), suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity. This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity-although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.

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(a) Experiment 3: mice received intraperitoneal (i.p.) codeine (n=16, 21 mg kg−1) or morphine (n=16, 20 mg kg−1) twice daily for 4 days. Hyperalgesia (hotplate) and allodynia (von Frey) were measured on days 0, 3 and 5. Thirty minutes before assessments on day 5, half of the mice in each drug group received i.p. interleukin-1 receptor antagonist (IL-1RA, 100 mg kg−1) and the remaining half received saline. (a1) IL-1RA abolished decreases in paw-withdrawal latency in both the codeine and morphine groups at day 5 vs groups receiving saline. (a2) IL-1RA significantly attenuated allodynia induced by codeine and morphine on day 5 vs saline in the left hind paw. (b) Experiment 4: toll-like receptor-4  mutant mice received i.p. codeine (n=8, 21 mg kg−1), morphine (n=8, 20 mg kg−1) or saline (n=8) twice daily for 4 days. Hyperalgesia (hotplate) and allodynia (von Frey) were measured on days 0, 3 and 5. (b1) Codeine (P=0.996) and morphine (P>0.99) did not alter hotplate paw-withdrawal latency at day 5 vs baseline. Allodynia did not change significantly over time in (b2) saline (P=0.09), (b3) codeine (P=0.051) or (b4) morphine (P=0.21) groups. (c) Experiment 5: mice received i.p. codeine (n=16, 21 mg kg−1) or morphine (n=16, 20 mg kg−1) twice daily for 4 days. On days 3 and 4, half of the mice in each group received i.p. ibudilast (15 mg kg−1) and the remaining half received vehicle twice daily. Hyperalgesia (hotplate) and allodynia (von Frey) were measured on days 0, 3 and 5. (c1) Ibudilast reversed decreases in hotplate paw-withdrawal latency in morphine but not codeine (P=0.2) animals at day 5 vs groups receiving saline in addition to their respective opioid. (c2) Ibudilast significantly attenuated allodynia induced by codeine and morphine in the von Frey test on day 5 vs saline in the left hind paw. Total allodynia was measured by calculating the slope and intercept for the plot of number of paw withdrawals per 10 applications vs von Frey stimulus for each group. ***P<0.001.
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fig3: (a) Experiment 3: mice received intraperitoneal (i.p.) codeine (n=16, 21 mg kg−1) or morphine (n=16, 20 mg kg−1) twice daily for 4 days. Hyperalgesia (hotplate) and allodynia (von Frey) were measured on days 0, 3 and 5. Thirty minutes before assessments on day 5, half of the mice in each drug group received i.p. interleukin-1 receptor antagonist (IL-1RA, 100 mg kg−1) and the remaining half received saline. (a1) IL-1RA abolished decreases in paw-withdrawal latency in both the codeine and morphine groups at day 5 vs groups receiving saline. (a2) IL-1RA significantly attenuated allodynia induced by codeine and morphine on day 5 vs saline in the left hind paw. (b) Experiment 4: toll-like receptor-4 mutant mice received i.p. codeine (n=8, 21 mg kg−1), morphine (n=8, 20 mg kg−1) or saline (n=8) twice daily for 4 days. Hyperalgesia (hotplate) and allodynia (von Frey) were measured on days 0, 3 and 5. (b1) Codeine (P=0.996) and morphine (P>0.99) did not alter hotplate paw-withdrawal latency at day 5 vs baseline. Allodynia did not change significantly over time in (b2) saline (P=0.09), (b3) codeine (P=0.051) or (b4) morphine (P=0.21) groups. (c) Experiment 5: mice received i.p. codeine (n=16, 21 mg kg−1) or morphine (n=16, 20 mg kg−1) twice daily for 4 days. On days 3 and 4, half of the mice in each group received i.p. ibudilast (15 mg kg−1) and the remaining half received vehicle twice daily. Hyperalgesia (hotplate) and allodynia (von Frey) were measured on days 0, 3 and 5. (c1) Ibudilast reversed decreases in hotplate paw-withdrawal latency in morphine but not codeine (P=0.2) animals at day 5 vs groups receiving saline in addition to their respective opioid. (c2) Ibudilast significantly attenuated allodynia induced by codeine and morphine in the von Frey test on day 5 vs saline in the left hind paw. Total allodynia was measured by calculating the slope and intercept for the plot of number of paw withdrawals per 10 applications vs von Frey stimulus for each group. ***P<0.001.

Mentions: A significant overall effect of intervention (IL-1RA or saline) was detected in both hotplate (P<0.001) and von Frey (P<0.001) tests. As illustrated in Figure 3a1, both codeine and morphine when given with saline only produced significant hyperalgesia (P<0.001 and P<0.001, respectively) at day 5 vs baseline. In codeine and morphine animals receiving IL-1RA before the final hyperalgesia assessment on day 5, paw-withdrawal latency began to return to baseline levels for both opioid groups, with morphine+IL-RA vs morphine+saline (P<0.001) and codeine+IL-RA vs codeine+saline (P<0.001) reaching significance. In the von Frey test, codeine and morphine, given with saline, established allodynia on day 5 vs baseline (P<0.001 and P<0.001, respectively). Partially established allodynia in codeine and morphine groups was abolished by IL-RA on day 5, as depicted in Figure 3a2.


Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation.

Johnson JL, Rolan PE, Johnson ME, Bobrovskaya L, Williams DB, Johnson K, Tuke J, Hutchinson MR - Transl Psychiatry (2014)

(a) Experiment 3: mice received intraperitoneal (i.p.) codeine (n=16, 21 mg kg−1) or morphine (n=16, 20 mg kg−1) twice daily for 4 days. Hyperalgesia (hotplate) and allodynia (von Frey) were measured on days 0, 3 and 5. Thirty minutes before assessments on day 5, half of the mice in each drug group received i.p. interleukin-1 receptor antagonist (IL-1RA, 100 mg kg−1) and the remaining half received saline. (a1) IL-1RA abolished decreases in paw-withdrawal latency in both the codeine and morphine groups at day 5 vs groups receiving saline. (a2) IL-1RA significantly attenuated allodynia induced by codeine and morphine on day 5 vs saline in the left hind paw. (b) Experiment 4: toll-like receptor-4  mutant mice received i.p. codeine (n=8, 21 mg kg−1), morphine (n=8, 20 mg kg−1) or saline (n=8) twice daily for 4 days. Hyperalgesia (hotplate) and allodynia (von Frey) were measured on days 0, 3 and 5. (b1) Codeine (P=0.996) and morphine (P>0.99) did not alter hotplate paw-withdrawal latency at day 5 vs baseline. Allodynia did not change significantly over time in (b2) saline (P=0.09), (b3) codeine (P=0.051) or (b4) morphine (P=0.21) groups. (c) Experiment 5: mice received i.p. codeine (n=16, 21 mg kg−1) or morphine (n=16, 20 mg kg−1) twice daily for 4 days. On days 3 and 4, half of the mice in each group received i.p. ibudilast (15 mg kg−1) and the remaining half received vehicle twice daily. Hyperalgesia (hotplate) and allodynia (von Frey) were measured on days 0, 3 and 5. (c1) Ibudilast reversed decreases in hotplate paw-withdrawal latency in morphine but not codeine (P=0.2) animals at day 5 vs groups receiving saline in addition to their respective opioid. (c2) Ibudilast significantly attenuated allodynia induced by codeine and morphine in the von Frey test on day 5 vs saline in the left hind paw. Total allodynia was measured by calculating the slope and intercept for the plot of number of paw withdrawals per 10 applications vs von Frey stimulus for each group. ***P<0.001.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4259992&req=5

fig3: (a) Experiment 3: mice received intraperitoneal (i.p.) codeine (n=16, 21 mg kg−1) or morphine (n=16, 20 mg kg−1) twice daily for 4 days. Hyperalgesia (hotplate) and allodynia (von Frey) were measured on days 0, 3 and 5. Thirty minutes before assessments on day 5, half of the mice in each drug group received i.p. interleukin-1 receptor antagonist (IL-1RA, 100 mg kg−1) and the remaining half received saline. (a1) IL-1RA abolished decreases in paw-withdrawal latency in both the codeine and morphine groups at day 5 vs groups receiving saline. (a2) IL-1RA significantly attenuated allodynia induced by codeine and morphine on day 5 vs saline in the left hind paw. (b) Experiment 4: toll-like receptor-4 mutant mice received i.p. codeine (n=8, 21 mg kg−1), morphine (n=8, 20 mg kg−1) or saline (n=8) twice daily for 4 days. Hyperalgesia (hotplate) and allodynia (von Frey) were measured on days 0, 3 and 5. (b1) Codeine (P=0.996) and morphine (P>0.99) did not alter hotplate paw-withdrawal latency at day 5 vs baseline. Allodynia did not change significantly over time in (b2) saline (P=0.09), (b3) codeine (P=0.051) or (b4) morphine (P=0.21) groups. (c) Experiment 5: mice received i.p. codeine (n=16, 21 mg kg−1) or morphine (n=16, 20 mg kg−1) twice daily for 4 days. On days 3 and 4, half of the mice in each group received i.p. ibudilast (15 mg kg−1) and the remaining half received vehicle twice daily. Hyperalgesia (hotplate) and allodynia (von Frey) were measured on days 0, 3 and 5. (c1) Ibudilast reversed decreases in hotplate paw-withdrawal latency in morphine but not codeine (P=0.2) animals at day 5 vs groups receiving saline in addition to their respective opioid. (c2) Ibudilast significantly attenuated allodynia induced by codeine and morphine in the von Frey test on day 5 vs saline in the left hind paw. Total allodynia was measured by calculating the slope and intercept for the plot of number of paw withdrawals per 10 applications vs von Frey stimulus for each group. ***P<0.001.
Mentions: A significant overall effect of intervention (IL-1RA or saline) was detected in both hotplate (P<0.001) and von Frey (P<0.001) tests. As illustrated in Figure 3a1, both codeine and morphine when given with saline only produced significant hyperalgesia (P<0.001 and P<0.001, respectively) at day 5 vs baseline. In codeine and morphine animals receiving IL-1RA before the final hyperalgesia assessment on day 5, paw-withdrawal latency began to return to baseline levels for both opioid groups, with morphine+IL-RA vs morphine+saline (P<0.001) and codeine+IL-RA vs codeine+saline (P<0.001) reaching significance. In the von Frey test, codeine and morphine, given with saline, established allodynia on day 5 vs baseline (P<0.001 and P<0.001, respectively). Partially established allodynia in codeine and morphine groups was abolished by IL-RA on day 5, as depicted in Figure 3a2.

Bottom Line: Chronic morphine therapy has been associated with paradoxically increased pain.IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity.Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.

View Article: PubMed Central - PubMed

Affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, SA, Australia.

ABSTRACT
Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. In silico docking simulations indicate codeine also docks to MD2, an accessory protein for TLR4, suggesting potential to induce TLR4-dependent pain facilitation. We hypothesized codeine would cause TLR4-dependent hyperalgesia/allodynia that is disparate from its opioid receptor-dependent analgesic rank potency. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests at days 0, 3 and 5 in mice receiving intraperitoneal equimolar codeine (21 mg kg(-1)), morphine (20 mg kg(-1)) or saline, twice daily. This experiment was repeated in animals with prior partial nerve injury and in TLR4 mutant mice. Interventions with interleukin-1 receptor antagonist (IL-1RA) and glial-attenuating drug ibudilast were assessed. Analyses of glial activation markers (glial fibrillary acid protein and CD11b) in neuronal tissue were conducted at the completion of behavioural testing. Despite providing less acute analgesia (P=0.006), codeine induced similar hotplate hyperalgesia to equimolar morphine vs saline (-9.5 s, P<0.01 and -7.3 s, P<0.01, respectively), suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity. This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity-although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.

Show MeSH
Related in: MedlinePlus