The cAMP pathway and pain: potential targets for drug development

Skyba, David A.; Radhakrishnan, Rajan; Bement, Marie Hoeger; Sluka, Kathleen A.

doi:10.1016/j.ddmod.2004.07.003

Cited by 6 publications

(4 citation statements)

References 26 publications

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“…cAMP pathway in G-protein dependant manner is associated with nociception [53] . Increased cAMP is allied with behavioural symptoms of withdrawal and enhanced action potential in neurons [54] .…”

Section: Discussionmentioning

confidence: 99%

δ-Opioid Receptor and Somatostatin Receptor-4 Heterodimerization: Possible Implications in Modulation of Pain Associated Signaling

Somvanshi

Kumar

2014

PLoS ONE

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Pain relief is the principal action of opioids. Somatostatin (SST), a growth hormone inhibitory peptide is also known to alleviate pain even in cases when opioids fail. Recent studies have shown that mice are prone to sustained pain and devoid of analgesic effect in the absence of somatostatin receptor 4 (SSTR4). In the present study, using brain slices, cultured neurons and HEK-293 cells, we showed that SSTR4 and δ-Opioid receptor (δOR) exist in a heteromeric complex and function in synergistic manner. SSTR4 and δOR co-expressed in cortical/striatal brain regions and spinal cord. Using cultured neuronal cells, we describe the heterogeneous complex formation of SSTR4 and δOR at neuronal cell body and processes. Cotransfected cells display inhibition of cAMP/PKA and co-activation of SSTR4 and δOR oppose receptor trafficking induced by individual receptor activation. Furthermore, downstream signaling pathways either associated with withdrawal or pain relief are modulated synergistically with a predominant role of SSTR4. Inhibition of cAMP/PKA and activation of ERK1/2 are the possible cellular adaptations to prevent withdrawal induced by chronic morphine use. Our results reveal direct intra-membrane interaction between SSTR4 and δOR and provide insights for the molecular mechanism for the anti-nociceptive property of SST in combination with opioids as a potential therapeutic approach to avoid undesirable withdrawal symptoms.

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Section: Discussionmentioning

confidence: 99%

δ-Opioid Receptor and Somatostatin Receptor-4 Heterodimerization: Possible Implications in Modulation of Pain Associated Signaling

Somvanshi

Kumar

2014

PLoS ONE

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“…A clear role for cyclic AMP has been established in the sensitization of nociceptors and pain projection neurons in the spinal cord after noxious stimulation and inflammation (reviewed in [142,143]). However the AC isoforms that contribute to these processes have been only recently studied.…”

Section: Synaptic Plasticity Associated With Painmentioning

confidence: 99%

“…The question still remains as to where AC isoforms are exerting their effects. Pharmacological studies support spinal cord as a major site of action [142]; AC 1 and 5 are expressed in spinal cord in addition to AC 2, 6, and 8 [146]. Although AC1 and AC5 display strong differences in their regulation, both are inhibited by PAM.…”

Section: Synaptic Plasticity Associated With Painmentioning

confidence: 99%

Physiological Roles for G Protein-Regulated Adenylyl Cyclase Isoforms: Insights from Knockout and Overexpression Studies

Sadana¹,

Dessauer²

2009

Neurosignals

323

343

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Cyclic AMP is a universal second messenger, produced by a family of adenylyl cyclase (AC) enzymes. The last three decades have brought a wealth of new information about the regulation of cyclic AMP production by ACs. Nine hormone-sensitive, membrane-bound AC isoforms have been identified in addition to a tenth isoform that lacks membrane spans and more closely resembles the cyanobacterial AC enzymes. New model systems for purifying and characterizing the catalytic domains of AC have led to the crystal structure of these domains and the mapping of numerous interaction sites. However, big hurdles remain in unraveling the roles of individual AC isoforms and their regulation in physiological systems. In this review we explore the latest on AC knockout and overexpression studies to better understand the roles of G protein regulation of ACs in the brain, olfactory bulb, and heart.

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“…Thus, the lower dose could activate mPRδ and mPRε, while 16 µg/kg dose would also activate mPRα. Both mPRδ and mPRε are stimulatory G-protein coupled receptors (GPCR) that increase in cAMP production (Hanna et al, 2006), which is associated with an increase in nociception (for review see Skyba et al, 2004). We elucidate that 16 ng/kg progesterone dose acting at mPRδ and mPRε would have pronociceptive properties via increased cAMP production, which could explain why this dose did not protect against the return of mechanical allodynia.…”

Section: Discussionmentioning

confidence: 94%

Progesterone and Allopregnanolone Rapidly Attenuate Estrogen-Associated Mechanical Allodynia in Rats with Persistent Temporomandibular Joint Inflammation

Hornung

Benton

Tongkhuya

et al. 2020

Front. Integr. Neurosci.

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Temporomandibular joint disorder (TMD) is associated with pain in the joint (temporomandibular joint, TMJ) and muscles involved in mastication. TMD pain dissipates following menopause but returns in some women undergoing estrogen replacement therapy. Progesterone has both anti-inflammatory and antinociceptive properties, while estrogen's effects on nociception are variable and highly dependent on both natural hormone fluctuations and estrogen dosage during pharmacological treatments, with high doses increasing pain. Allopregnanolone, a progesterone metabolite and positive allosteric modulator of the GABA A receptor, also has antinociceptive properties. While progesterone and allopregnanolone are antinociceptive, their effect on estrogen-exacerbated TMD pain has not been determined. We hypothesized that removing the source of endogenous ovarian hormones would reduce inflammatory allodynia in the TMJ of rats and both progesterone and allopregnanolone would attenuate the estrogen-provoked return of allodynia. Baseline mechanical sensitivity was measured in female Sprague-Dawley rats (150-175 g) using the von Frey filament method followed by a unilateral injection of complete Freund's adjuvant (CFA) into the TMJ. Mechanical allodynia was confirmed 24 h later; then rats were ovariectomized or received sham surgery. Two weeks later, allodynia was reassessed and rats received one of the following subcutaneous hormone treatments over 5 days: a daily pharmacological dose of estradiol benzoate (E2; 50 µg/kg), daily E2 and pharmacological to sub-physiological doses of progesterone (P4; 16 mg/kg, 16 µg/kg, or 16 ng/kg), E2 daily and interrupted P4 given every other day, daily P4, or daily vehicle control. A separate group of animals received allopregnanolone (0.16 mg/kg) instead of P4. Allodynia was reassessed 1 h following injections. Here, we report that CFA-evoked mechanical allodynia was attenuated following ovariectomy and daily high E2 treatment triggered the return of allodynia, which was rapidly attenuated when P4 was also administered either daily or every other day. Allopregnanolone treatment, whether daily or every other day, also attenuated estrogen-exacerbated

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The cAMP pathway and pain: potential targets for drug development

Cited by 6 publications

References 26 publications

δ-Opioid Receptor and Somatostatin Receptor-4 Heterodimerization: Possible Implications in Modulation of Pain Associated Signaling

δ-Opioid Receptor and Somatostatin Receptor-4 Heterodimerization: Possible Implications in Modulation of Pain Associated Signaling

Physiological Roles for G Protein-Regulated Adenylyl Cyclase Isoforms: Insights from Knockout and Overexpression Studies

Progesterone and Allopregnanolone Rapidly Attenuate Estrogen-Associated Mechanical Allodynia in Rats with Persistent Temporomandibular Joint Inflammation

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