Study
Species
Pain model
Dose of morphine and route of administration
Confirmed analgesic effect of morphine
Time in chamber during drug pairing
Morphine CPP outcome in subjects with chronic pain
Shippenburg [40]
Male Sprague Dawley rat, Charles River, Wiga, Germany
CFA, unilateral hindpaw injection
0.3, 1, 3, 5 mg/kg, S.C.
Yes, paw pressure threshold (Randall-Selitto)
60 min
No change
Sufka [52]
Male Sprague Dawley rat, Harlan, IN
CFA, unilateral hindpaw injection
3, 10 mg/kg
Yes, hot plate
60 min
Enhanced
Suzuki [45]
Male Sprague Dawley rats (Tokyo Experimental Animals)
Formalin, carrageenan
2, 4, 8 mg/kg, S.C.
Yes, paw pressure threshold (Randall-Selitto)
50 min
Suppressed
Oe [53]
Male ICR mice (Tokyo Experimental Animals)
PKC activator PDBU (1, 5, 10 nmol 5 day thermal hyperalgesia)
3, 5, 10 mg/kg, S.C.
Yes, hot plate (55 °C)
60 min
Suppressed
Ozaki [48]
Male Sprague Dawley rats (Tokyo Experimental Animals)
Partial sciatic nerve ligation
4 or 8 mg/kg, S.C.
Not specifically assessed
60 min
Suppressed
Ozaki [49]
Male, ICR mice (Tokyo Experimental Animals)
Partial sciatic nerve ligation
3, 10, and 30 nmol/mouse, I.C.V.
Yes, tail flick test
60 min
Suppressed
Ozaki [46]
Male ICR mice (Tokyo Experimental Animals)
Partial sciatic nerve ligation
2.5, 5, 10 mg/kg, S.C.
Not specifically assessed
60 min
Suppressed
Niikura [47]
Mice: male and female C57BL/6J and 129S2/SvPas mixed background
Partial sciatic nerve ligation
5 mg/kg, S.C.
Not specifically assessed
60 min
Suppressed
Narita [51]
Rats: Sprague Dawley (Tokyo Experimental Animals)
Formalin unilateral hindpaw
2, 4, 8 mg I.P.
Not specifically assessed
60 min
Suppressed
Petraschka [29]
Male C57BL/6 mice (Charles River Laboratories, Wilmington, MA, USA)
Partial sciatic nerve ligation
2.5, 5 mg/kg, S.C.
Yes, tail flick test
30 min
Suppressed
Betourne [44]
Female C57BL/6 mice (Iffa Credo, L’Arbresle, France)
Cancer (melanoma cell) CFA
10 mg/kg, I.P.
Yes, hindpaw licking
20 min
Suppressed: cancer, CFA
Carrageenan
No change: carrageenan
Cahill et al. [43]
Male Long Evans rat (Charles River, St. Constant, Quebec)
Chronic constriction injury
1, 2, 4, 8 mg/kg, S.C.
Yes, effective by 30 min
60 min
Enhanced
Non-Opioid Reinforcing Analgesics: Cannabinoid
In addition to consideration of opioids, NSAIDS, and corticosteroid classes of medications, Gutierrez and colleagues [54] have compared the self-administration pattern of a selective agonist for the cannabinoid 2 receptor in neuropathic rats versus two distinct controls, sham-operated and naïve rats. Following the development of tactile allodynia, the rats were placed in daily sessions over 4 days where they could bar press either of two levers. Pressing one of the levers does not result in any outcome, pressing the other lever resulted in an intravenous infusion of the CB2 receptor agonist (R, S)-AM1241. Unlike the opioid analgesics, but similar to NSAID analgesics, normal rats did not develop a preference for either lever. Neuropathic rats, however, showed lever-pressing preference for (R, S)-AM1241 i.v. delivery (but not vehicle), which alleviated tactile hypersensitivity measured following conclusion of each session. These data suggest that the lever pressing responses in neuropathic rats could be associated with the analgesic response of (R, S)-AM1241 delivery. An important observation noted in this study was that sham-operated rats (a common control for nerve injury models) also displayed active lever discrimination for intravenous (R, S)-AM1241. It is not very common for studies to include both naïve and sham-operated controls and so these findings are important for consideration of what the sham-operated control may represent. Sham-operated controls receive the same experience as nerve-injured rats in terms of anesthesia, incision, and all mechanical aspects of the surgery except the nerve injury itself. One might expect that there should be an aspect of postoperative pain that may not be detected in the standard reflex measurements and may (or may not) persist into the time of self-administration experimentation. We have similarly observed [38] an effect on self-administration in sham-operated subjects that may be interpreted as intermediate between nerve injured and naïve subjects. The primary importance of the contribution of Gutierrez and colleagues is to demonstrate that, like other non-opioid analgesic agents, the CB2 selective receptor agonist induced a lever preference that appears to be closely associated with analgesic benefit.
Conclusion
A prevalent observation from this review of over three decades of research appears to be that responding for opioids is different in subjects with chronic pain than subjects without chronic pain. As described above, that theme is observed repeatedly in many different experiments, across species, and pain-inducing conditions. These observations call for much greater investigation of opioid responding under conditions of chronic pain, identification and full characterization of the CNS altered systems so that the appropriate context can be considered when developing and optimizing patient pain management protocols. Currently, the discourse on patient response to opioid analgesics is primarily informed by our extensive decades-old literature on patient, nonhuman primate, and rodent responding to opioids under presumed pain-free conditions. Consideration of any alteration in the responding of chronic pain patients to opioid analgesics relative to the pain free human population has been acknowledged clinically for decades [2–4], but is eclipsed by our immensely greater knowledge and appropriate concern regarding the addictive properties of opioids in people without established chronic pain conditions. Second, experimental subjects with induced persistent pain, in many cases, appear to intentionally self-administer or seek the state of pain relief whether achieved by opioid or non-opioid analgesics. In other cases, opioid responding is diminished. This may be due to alterations in the reward pathways as is discussed further in this volume by Narita and colleagues in Chap. 4 of this volume. The general consensus of the literature reviewed here is that pain relief is reinforcing or motivational. It is essential to significantly expand our consideration of the alterations in subjects’ responding for opioid and other analgesics under diverse states of chronic pain in order to more fully address this public health concern from a scientific and objective platform.
References
1.
IOM. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington, DC: The National Academies Press; 2011.
3.
5.
6.
Weissman DE, Haddox JD. Opioid pseudoaddiction—an iatrogenic syndrome. Pain. 1989;36: 363–6.PubMedCrossRef
Related posts:
Biopharmaceutical Considerations of Opioid Analgesics in Models of Self-Administration: Review and Summary
Prenatal Exposure to Opioids
Opioid Self-Administration in the Presence of Chronic Pain: Analgesia or Addiction?
Opioids in an Evidence-Based World
Drug Addiction and Chronic Pain: A Review of Animal Models
Chronic Pain Stimuli Downregulate Mesolimbic Dopaminergic Transmission: Possible Mechanism of the Suppression of Opioid Reward
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