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. 2015 Apr;41(7):901--7.
doi: 10.1111/ejn.12829. Epub 2015 Jan 9.

Implication of delta opioid receptor subtype 2 but not delta opioid receptor subtype 1 in the development of morphine analgesic tolerance in a rat model of chronic inflammatory pain

H Beaudry  1 , L Gendron, J A Morón
Affiliations

Implication of delta opioid receptor subtype 2 but not delta opioid receptor subtype 1 in the development of morphine analgesic tolerance in a rat model of chronic inflammatory pain

H Beaudry et al. Eur J Neurosci. 2015 Apr.

Abstract

Opioids are well known for their robust analgesic effects. Chronic activation of mu opioid receptors (MOPs) is, however, accompanied by various unwanted effects such as analgesic tolerance. Among other mechanisms, interactions between MOPs and delta opioid receptors (DOPs) are thought to play an important role in morphine-induced behavioral adaptations. Interestingly, certain conditions such as inflammation enhance the function of the DOP through a MOP-dependent mechanism. Here, we investigated the role of DOPs during the development of morphine tolerance in an animal model of chronic inflammatory pain. Using behavioral approaches, we first established that repeated systemic morphine treatment induced morphine analgesic tolerance in rats coping with chronic inflammatory pain. We then observed that blockade of DOPs with subcutaneous naltrindole (NTI), a selective DOP antagonist, significantly attenuated the development of morphine tolerance in a dose-dependent manner. We confirmed that this effect was DOP mediated by showing that an acute injection of NTI had no effect on morphine-induced analgesia in naive animals. Previous pharmacological characterizations revealed the existence of DOP subtype 1 and DOP subtype 2. As opposed to NTI, 7-benzylidenenaltrexone and naltriben were reported to be selective DOP subtype 1 and DOP subtype 2 antagonists, respectively. Interestingly, naltriben but not 7-benzylidenenaltrexone was able to attenuate the development of morphine analgesic tolerance in inflamed rats. Altogether, our results suggest that targeting of DOP subtype 2 with antagonists provides a valuable strategy to attenuate the analgesic tolerance that develops after repeated morphine administration in the setting of chronic inflammatory pain.

Keywords: antagonist; heteromer; hyperalgesia; inflammation; opioid.

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Figures

Figure 1
Figure 1. Timeline representation of drug administration and behavioral measurements
Basal latencies to paw withdrawal were measured before CFA administration (Baseline pre CFA) and CFA was injected in the left hindpaw. Twelve hours later, DOP antagonist or vehicle (A) was administered s.c. 15 min before morphine 10 mg/kg or vehicle (M) every 12h for 5 consecutive injections. Twelve hours after the last A+M treatment, thermal latencies to paw withdrawal were measured (Baseline CFA) and Hargreaves test was performed as described in the text.
Figure 2
Figure 2. Effect of acute NTI injection on morphine antihyperalgesic effect in inflamed rats
Sprague–Dawley rats were injected with CFA in the plantar surface of the hind paw. Seventy-two hours after CFA injection, the latency to paw withdrawal (in sec) was tested before (Baseline) and after (0) a pretreatment with NTI or saline (s.c.; 15 min) using the Hargreaves test. Morphine 3 mg/kg (Morphine) was administered in both groups to compare morphine’s antihyperalgesic effect every 15 min (from 15 to 60 min). Number given in the legend inset represents the number of animals per group. Acute NTI did not modify morphine antihyperalgesic effect.
Figure 3
Figure 3. Determination of NTI dose necessary to prevent morphine analgesic tolerance in inflamed rats
CFA inflamed rats were pretreated as illustrated in Fig. 1 with NTI (0.003 to 0.3 mg/kg) as a DOP antagonist. Twelve hours after the last pretreatment injection (saline followed 15 min later by saline (□), saline followed 15 min later by morphine (■) or three different doses of NTI (■)), the analgesic effect of a challenging dose of morphine (3 mg/kg) was measured using the Hargreaves test. Results are expressed as area under curve obtained between 0 and 60 min after morphine challenge dose (Y baseline set for each animal according to its latency to paw withdrawal after inflammation). (N = 9–15 rats), *, p<0.05 and ***, p<0.001 when groups were compared to Saline/Morphine group. NTI at 0.03 mg/kg is sufficient to prevent morphine analgesic tolerance.
Figure 4
Figure 4. Effect of NTI pretreatment on morphine analgesic tolerance in inflamed rats
(A) CFA inflamed rats were pretreated as illustrated in Fig. 1 with NTI 0.3 mg/kg as a DOP antagonist. Twelve hours after the last treatment, the analgesic effect of a challenging dose of morphine (0.3 to 10 mg/kg) was measured using the Hargreaves test. Results are expressed as area under curve obtained between 0 and 60 min after morphine challenge dose (Y baseline set for each animal according to its latency to paw withdrawal after inflammation). (N = 8–13 rats), *, p<0.05 and ****, p<0.0001 when groups were compared together within a similar morphine challenge dose. (B) CFA inflamed rats were pretreated as illustrated in Fig. 1 with NTI 0.3 mg/kg as a DOP antagonist. Twelve hours after the last treatment, the analgesic effect of a challenging dose of morphine (3 mg/kg) was measured using the Hargreaves test. The latency to paw withdrawal (in sec) was tested every 15 min (from 0 to 60 min) after morphine injection. Number given in the legend inset represents the number of animals per group. **, p<0.01 and ***, p<0.001 when groups were compared together. NTI pretreatment prevented morphine analgesic tolerance in inflamed rats.
Figure 5
Figure 5. Effect of BNTX and NTB pretreatment on morphine analgesic tolerance in inflamed rats
(A) CFA inflamed rats were pretreated as illustrated in Fig. 1 with BNTX 1 mg/kg or NTB 0.1 mg/kg as DOP antagonists. Twelve hours after the last treatment, the analgesic effect of a challenging dose of morphine (3 mg/kg) was measured using the Hargreaves test. The latency to paw withdrawal (in sec) was tested every 15 min (from 0 to 60 min) after morphine injection. Number given in the legend inset represents the number of animals per group. *, p<0.05 and ****, p<0.0001 when groups were compared to Saline/Morphine group. (B) Results obtained with the three DOP selective antagonists are expressed as area under curve obtained between 0 and 60 min after morphine challenge dose (Y baseline set for each animal according to its latency to paw withdrawal after inflammation). Dashed lined represent AUC obtained for control Saline/Saline group. (N = 8–13 rats). *, p<0.05 and **, p<0.01 when groups were compared to Saline/Morphine group. Chronic injections of NTI and NTB, but not BNTX, prevented morphine analgesic tolerance in inflamed-rats and the morphine analgesic efficacy in NTI- or NTB-pretreated rats reached the efficacy obtained in control rats.
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