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The combined predictive capacity of rat models of algogen-induced and neuropathic hypersensitivity to clinically used analgesics varies with nociceptive endpoint and consideration of locomotor function.
Pharmacol Biochem Behav. 2012 May; 101(3):465-78.PB

Abstract

Different neurobiological mechanism(s) might contribute to evoked and non-evoked pains and to limited translational drug discovery efforts. Other variables including the pain model and sensory testing method used, dose/route/preadministration time of compound(s), lack of adverse effect profiling and level of observer experience might also contribute. With these points in mind, we tested three mechanistically distinct analgesics in rat models of algogen-induced and neuropathic pain. In chronic constriction injury (CCI) rats evoked hindpaw mechanical hypersensitivity and spontaneous weight bearing deficits developed quickly and persisted for at least 3 weeks post-injury. In contrast, evoked cold hypersensitivity, or movement-associated behavioural deficits (rotarod, beam-walking) were less manifested or dissipated rapidly post-injury. Mechanical hypersensitivity was dose-dependently reversed by morphine (3-10 mg/kg, s.c.) and gabapentin (50-200 mg/kg, i.p.). Weight bearing deficits and cold hypersensitivity were reversed only by high doses of each drug. Surprisingly, duloxetine (10-60 mg/kg, s.c.) was largely ineffective in neuropathic rats although it partially reduced formalin-induced spontaneous nocifensive behaviours; especially during interphase, a period associated with activation of descending monoaminergic inhibition. Morphine and gabapentin markedly attenuated second phase formalin- and in addition capsaicin-induced nocifensive behaviours; indicative of effects on central sensitization and nociceptor hyperexcitability mechanisms. Only gabapentin consistently attenuated nociceptive behaviours at a dose that did not impair exploratory locomotor behaviour in naïve rats. Accordingly, this comparative analysis indicates that the pharmacological sensitivity of evoked and non-evoked pain indices does not necessarily correlate within models, perhaps reflecting differing underlying mechanisms. Conversely, the pharmacological specificity of non-evoked pain indices to selected drugs was conserved across models indicative of similar underlying mechanisms enduring in the face of differing aetiology. Finally, although the predictive capacity of these models was largely unaffected by observer-related experience, it was putatively compromised when adverse event profiling of each drug was considered in parallel.

Authors+Show Affiliations

NeuroSearch A/S, 93 Pederstrupvej, DK-2750 Ballerup, Denmark. gmun@lundbeck.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22366217

Citation

Munro, Gordon, et al. "The Combined Predictive Capacity of Rat Models of Algogen-induced and Neuropathic Hypersensitivity to Clinically Used Analgesics Varies With Nociceptive Endpoint and Consideration of Locomotor Function." Pharmacology, Biochemistry, and Behavior, vol. 101, no. 3, 2012, pp. 465-78.
Munro G, Storm A, Hansen MK, et al. The combined predictive capacity of rat models of algogen-induced and neuropathic hypersensitivity to clinically used analgesics varies with nociceptive endpoint and consideration of locomotor function. Pharmacol Biochem Behav. 2012;101(3):465-78.
Munro, G., Storm, A., Hansen, M. K., Dyhr, H., Marcher, L., Erichsen, H. K., & Sheykhzade, M. (2012). The combined predictive capacity of rat models of algogen-induced and neuropathic hypersensitivity to clinically used analgesics varies with nociceptive endpoint and consideration of locomotor function. Pharmacology, Biochemistry, and Behavior, 101(3), 465-78. https://doi.org/10.1016/j.pbb.2012.02.008
Munro G, et al. The Combined Predictive Capacity of Rat Models of Algogen-induced and Neuropathic Hypersensitivity to Clinically Used Analgesics Varies With Nociceptive Endpoint and Consideration of Locomotor Function. Pharmacol Biochem Behav. 2012;101(3):465-78. PubMed PMID: 22366217.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The combined predictive capacity of rat models of algogen-induced and neuropathic hypersensitivity to clinically used analgesics varies with nociceptive endpoint and consideration of locomotor function. AU - Munro,Gordon, AU - Storm,Ann, AU - Hansen,Merete K, AU - Dyhr,Helene, AU - Marcher,Lotte, AU - Erichsen,Helle K, AU - Sheykhzade,Majid, Y1 - 2012/02/16/ PY - 2011/11/24/received PY - 2012/01/26/revised PY - 2012/02/11/accepted PY - 2012/2/28/entrez PY - 2012/3/1/pubmed PY - 2012/8/3/medline SP - 465 EP - 78 JF - Pharmacology, biochemistry, and behavior JO - Pharmacol Biochem Behav VL - 101 IS - 3 N2 - Different neurobiological mechanism(s) might contribute to evoked and non-evoked pains and to limited translational drug discovery efforts. Other variables including the pain model and sensory testing method used, dose/route/preadministration time of compound(s), lack of adverse effect profiling and level of observer experience might also contribute. With these points in mind, we tested three mechanistically distinct analgesics in rat models of algogen-induced and neuropathic pain. In chronic constriction injury (CCI) rats evoked hindpaw mechanical hypersensitivity and spontaneous weight bearing deficits developed quickly and persisted for at least 3 weeks post-injury. In contrast, evoked cold hypersensitivity, or movement-associated behavioural deficits (rotarod, beam-walking) were less manifested or dissipated rapidly post-injury. Mechanical hypersensitivity was dose-dependently reversed by morphine (3-10 mg/kg, s.c.) and gabapentin (50-200 mg/kg, i.p.). Weight bearing deficits and cold hypersensitivity were reversed only by high doses of each drug. Surprisingly, duloxetine (10-60 mg/kg, s.c.) was largely ineffective in neuropathic rats although it partially reduced formalin-induced spontaneous nocifensive behaviours; especially during interphase, a period associated with activation of descending monoaminergic inhibition. Morphine and gabapentin markedly attenuated second phase formalin- and in addition capsaicin-induced nocifensive behaviours; indicative of effects on central sensitization and nociceptor hyperexcitability mechanisms. Only gabapentin consistently attenuated nociceptive behaviours at a dose that did not impair exploratory locomotor behaviour in naïve rats. Accordingly, this comparative analysis indicates that the pharmacological sensitivity of evoked and non-evoked pain indices does not necessarily correlate within models, perhaps reflecting differing underlying mechanisms. Conversely, the pharmacological specificity of non-evoked pain indices to selected drugs was conserved across models indicative of similar underlying mechanisms enduring in the face of differing aetiology. Finally, although the predictive capacity of these models was largely unaffected by observer-related experience, it was putatively compromised when adverse event profiling of each drug was considered in parallel. SN - 1873-5177 UR - https://www.unboundmedicine.com/medline/citation/22366217/The_combined_predictive_capacity_of_rat_models_of_algogen_induced_and_neuropathic_hypersensitivity_to_clinically_used_analgesics_varies_with_nociceptive_endpoint_and_consideration_of_locomotor_function_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-3057(12)00050-0 DB - PRIME DP - Unbound Medicine ER -