Spinal or systemic TY005, a peptidic opioid agonist/neurokinin 1 antagonist, attenuates pain with reduced tolerance

T. M. Largent-Milnes, T. Yamamoto, P. Nair, J. W. Moulton, Victor J Hruby, J. Lai, Frank Porreca, Todd W Vanderah

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE The use of opioids in treating pain is limited due to significant side effects including somnolence, constipation, analgesic tolerance, addiction and respiratory depression. Pre-clinical studies have shown that neurokinin 1 (NK 1) receptor antagonists block opioid-induced antinociceptive tolerance and may inhibit opioid-induced rewarding behaviours. Here, we have characterized a bifunctional peptide with both opioid agonist and NK 1 antagonist pharmacophores in a rodent model of neuropathic pain. EXPERIMENTAL APPROACH Rats were evaluated for behavioural responses to both tactile and thermal stimuli in either an uninjured, sham- or nerve-injured state. TY005 (Tyr-DAla-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bn(CF 3) 2) was delivered spinally or systemically to assess the antinociceptive effects after acute exposure. Motor skills were evaluated using the rotarod test to determine potential sedative effects. Spinal TY005 was given chronically to sham- or nerve-injured animals to determine the development of tolerance. KEY RESULTS Bolus injections of TY005 produced dose-dependent antinociception in non-injured animals and alleviated nerve injury-induced thermal and tactile hypersensitivities (i.e. antihyperalgesia) more effectively than morphine. Sedative effects were not evident from the rotarod test at doses that were antihyperalgesic, nor at doses threefold higher. Repeated administration of TY005 did not lead to the development of antihyperalgesic tolerance or alter sensory thresholds. CONCLUSIONS AND IMPLICATIONS Collectively, the data suggest that opioid agonist/NK 1 antagonist bifunctional peptides represent a promising novel approach to the management of chronic pain without the development of tolerance, reducing the need for escalation of doses and unwanted side effects associated with opiates alone.

Original languageEnglish (US)
Pages (from-to)986-1001
Number of pages16
JournalBritish Journal of Pharmacology
Volume161
Issue number5
DOIs
StatePublished - Nov 2010

Fingerprint

Opioid Analgesics
Pain
Rotarod Performance Test
Touch
Hypnotics and Sedatives
Opiate Alkaloids
Hot Temperature
Neurokinin-1 Receptor Antagonists
Sensory Thresholds
Peptides
Motor Skills
Neuralgia
Constipation
Chronic Pain
Respiratory Insufficiency
Morphine
Analgesics
Rodentia
Hypersensitivity
Injections

Keywords

  • Antinociception
  • Neurokinin 1 receptor
  • Neuropathic pain
  • Opioids
  • Substance P
  • Tolerance

ASJC Scopus subject areas

  • Pharmacology

Cite this

Spinal or systemic TY005, a peptidic opioid agonist/neurokinin 1 antagonist, attenuates pain with reduced tolerance. / Largent-Milnes, T. M.; Yamamoto, T.; Nair, P.; Moulton, J. W.; Hruby, Victor J; Lai, J.; Porreca, Frank; Vanderah, Todd W.

In: British Journal of Pharmacology, Vol. 161, No. 5, 11.2010, p. 986-1001.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND AND PURPOSE The use of opioids in treating pain is limited due to significant side effects including somnolence, constipation, analgesic tolerance, addiction and respiratory depression. Pre-clinical studies have shown that neurokinin 1 (NK 1) receptor antagonists block opioid-induced antinociceptive tolerance and may inhibit opioid-induced rewarding behaviours. Here, we have characterized a bifunctional peptide with both opioid agonist and NK 1 antagonist pharmacophores in a rodent model of neuropathic pain. EXPERIMENTAL APPROACH Rats were evaluated for behavioural responses to both tactile and thermal stimuli in either an uninjured, sham- or nerve-injured state. TY005 (Tyr-DAla-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bn(CF 3) 2) was delivered spinally or systemically to assess the antinociceptive effects after acute exposure. Motor skills were evaluated using the rotarod test to determine potential sedative effects. Spinal TY005 was given chronically to sham- or nerve-injured animals to determine the development of tolerance. KEY RESULTS Bolus injections of TY005 produced dose-dependent antinociception in non-injured animals and alleviated nerve injury-induced thermal and tactile hypersensitivities (i.e. antihyperalgesia) more effectively than morphine. Sedative effects were not evident from the rotarod test at doses that were antihyperalgesic, nor at doses threefold higher. Repeated administration of TY005 did not lead to the development of antihyperalgesic tolerance or alter sensory thresholds. CONCLUSIONS AND IMPLICATIONS Collectively, the data suggest that opioid agonist/NK 1 antagonist bifunctional peptides represent a promising novel approach to the management of chronic pain without the development of tolerance, reducing the need for escalation of doses and unwanted side effects associated with opiates alone.",
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AU - Largent-Milnes, T. M.

AU - Yamamoto, T.

AU - Nair, P.

AU - Moulton, J. W.

AU - Hruby, Victor J

AU - Lai, J.

AU - Porreca, Frank

AU - Vanderah, Todd W

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AB - BACKGROUND AND PURPOSE The use of opioids in treating pain is limited due to significant side effects including somnolence, constipation, analgesic tolerance, addiction and respiratory depression. Pre-clinical studies have shown that neurokinin 1 (NK 1) receptor antagonists block opioid-induced antinociceptive tolerance and may inhibit opioid-induced rewarding behaviours. Here, we have characterized a bifunctional peptide with both opioid agonist and NK 1 antagonist pharmacophores in a rodent model of neuropathic pain. EXPERIMENTAL APPROACH Rats were evaluated for behavioural responses to both tactile and thermal stimuli in either an uninjured, sham- or nerve-injured state. TY005 (Tyr-DAla-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bn(CF 3) 2) was delivered spinally or systemically to assess the antinociceptive effects after acute exposure. Motor skills were evaluated using the rotarod test to determine potential sedative effects. Spinal TY005 was given chronically to sham- or nerve-injured animals to determine the development of tolerance. KEY RESULTS Bolus injections of TY005 produced dose-dependent antinociception in non-injured animals and alleviated nerve injury-induced thermal and tactile hypersensitivities (i.e. antihyperalgesia) more effectively than morphine. Sedative effects were not evident from the rotarod test at doses that were antihyperalgesic, nor at doses threefold higher. Repeated administration of TY005 did not lead to the development of antihyperalgesic tolerance or alter sensory thresholds. CONCLUSIONS AND IMPLICATIONS Collectively, the data suggest that opioid agonist/NK 1 antagonist bifunctional peptides represent a promising novel approach to the management of chronic pain without the development of tolerance, reducing the need for escalation of doses and unwanted side effects associated with opiates alone.

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