title: Withania somnifera root extract prolongs analgesia and suppresses hyperalgesia in mice treated with morphine.
abstract: Previous studies demonstrated that Withania somnifera Dunal (WS), a safe medicinal plant, prevents the development of tolerance to the analgesic effect of morphine. In the present study, we investigated whether WS extract (WSE) (100 mg/kg, i.p.) may also modulate the analgesic effect induced by acute morphine administration (2.5, 5, 10 mg/kg, s.c.) in the tail-flick and in the hot plate tests, and if it may prevent the development of 2.5 mg/kg morphine-induced rebound hyperalgesia in the low intensity tail-flick test. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for opioid (μ, δ, k), cannabinoid (CB1, CB2), glutamatergic (NMDA), GABAergic (GABAA, GABAB), serotoninergic (5HT2A) and adrenergic (α2) receptors. The results demonstrated that (i) WSE alone failed to alter basal nociceptive threshold in both tests, (ii) WSE pre-treatment significantly protracted the antinociceptive effect induced by 5 and 10 mg/kg of morphine only in tail-flick test, (iii) WSE pre-treatment prevented morphine-induced hyperalgesia in the low intensity tail-flick test, and (iv) WSE exhibited a high affinity for the GABAA and moderate affinity for GABAB, NMDA and δ opioid receptors. WSE prolongs morphine-induced analgesia and suppresses the development of morphine-induced rebound hyperalgesia probably through involvement of GABAA, GABAB, NMDA and δ opioid receptors. This study suggests the therapeutic potential of WSE as a valuable adjuvant agent in opioid-sparing therapies.
authors.affiliation: CNR-Institute of Translational Pharmacology, U.O.S. of Cagliari, Science and Technology Park of Sardinia Polaris, Pula, Italy. Electronic address: alessandro.orru@ift.cnr.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Orrù
authors.affiliation: CNR-Institute of Translational Pharmacology, U.O.S. of Cagliari, Science and Technology Park of Sardinia Polaris, Pula, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Marchese
authors.affiliation: CNR-Institute of Translational Pharmacology, U.O.S. of Cagliari, Science and Technology Park of Sardinia Polaris, Pula, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Casu
authors.affiliation: CNR-Institute of Translational Pharmacology, U.O.S. of Cagliari, Science and Technology Park of Sardinia Polaris, Pula, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Casu
authors.affiliation: Sanjivani College of Pharmaceutical Education & Research, Kopargaon, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kasture
authors.affiliation: Department of Life and Environmental Sciences - Drug Sciences Section, University of Cagliari, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Cottiglia
authors.affiliation: Department of Life and Environmental Sciences - Pharmaceutical, Pharmacological and Nutraceutical Sciences Section, University of Cagliari, Italy; Centre of Excellence on Neurobiology of Addiction, University of Cagliari, Italy; National Institute of Neuroscience - INN, University of Cagliari, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Acquas
authors.affiliation: CNR-Institute of Neuroscience, Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Mascia
authors.affiliation: Department of Life and Environmental Sciences - Drug Sciences Section, University of Cagliari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Anzani
authors.affiliation: CNR-Institute of Translational Pharmacology, U.O.S. of Cagliari, Science and Technology Park of Sardinia Polaris, Pula, Italy. Electronic address: stefania.ruiu@cnr.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ruiu
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use; D000818:Animals; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D008297:Male; D051379:Mice; D009020:Morphine / Q000627:therapeutic use; D059226:Nociceptive Pain / Q000188:drug therapy*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D010946:Plants, Medicinal; D017981:Receptors, Neurotransmitter / Q000819:agonists*; D032341:Withania
chemical_list: D000701:Analgesics, Opioid; D010936:Plant Extracts; D017981:Receptors, Neurotransmitter; D009020:Morphine
keywords: Antinociception; Binding assay; Hyperalgesia; Morphine; Withania somnifera